SYNTHESIS OF 9-(ARYLALKYL)-1,2,3,4-TETRAHYDRO-y-CARBOLINE AND ANALOGUES AND INTERMEDIATES

ABSTRACT

The present invention pertains generally to methods of preparing certain 9-(arylalkyl)-1,2,3,4-tetrahydro-γ-carboline compounds and their analogues, and especially to methods of preparing dimebon. The present invention also pertains to methods of preparing certain intermediate compounds which find use in the synthesis of the 9-(arylalkyl)-1,2,3,4-tetrahydro-γ-carboline compounds.

TECHNICAL FIELD

This invention pertains generally to processes, methods and materialsfor the preparation of particular pyridoindole compounds, such asdimebon. These compounds are useful as drugs, for example, in thetreatment of tauopathies, such as Alzheimer's disease.

BACKGROUND

A number of patents and publications are cited herein in order to morefully describe and disclose the invention and the state of the art towhich the invention pertains. Each of these references is incorporatedherein by reference in its entirety into the present disclosure, to thesame extent as if each individual reference was specifically andindividually indicated to be incorporated by reference.

Throughout this specification, including the claims which follow, unlessthe context requires otherwise, the word “comprise,” and variations suchas “comprises” and “comprising,” will be understood to imply theinclusion of a stated integer or step or group of integers or steps butnot the exclusion of any other integer or step or group of integers orsteps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a pharmaceutical carrier” includes mixtures of two or moresuch carriers, and the like.

Ranges are often expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by the use of the antecedent “about,” itwill be understood that the particular value forms another embodiment.

Dimebon, also referred to as dimebolin, and its structurally relatedanalogues have been shown to inhibit the death of brain cells inpreclinical models of Alzheimer's disease (AD) (see, for example,Medivation Form 10KSB filed 19 Feb. 2008). Treatment of patients havingmild-to-moderate AD in a randomised, double-blind, placebo-controlledstudy with dimebon is reported as resulting in significant benefits inassessed cognition, as measured in the cognitive subscale of theAlzheimer's disease assessment scale (ADAS-cog) (see Doody et al.). Itis suggested that dimebon is safe, well tolerated, and is capable ofimproving the clinical course of subjects having AD at a mild tomoderate level. Further clinical trials are underway for the use ofDimebon against Alzheimer's disease and for Huntington's disease (seeMedivation press release 4 Nov. 2009).

Dimebon has also been reported to be an inhibitor of TDP-43proteinopathy in cellular models of amyotrophic lateral sclerosis (ALS)and frontotemporal lobar degeneration with ubiquitinated inclusions(FLTD-U) (see Yamashita et al.).

Dimebon has the structure shown below, where the atoms in thepyridoindole group are labelled for reference:

A key intermediate in the synthesis of Dimebon and its analogues is[2-(6-methyl-pyridin-3-yl)-ethyl]-p-tolyl-amine (compound (1)). Thiscompound may be prepared from 2-methyl-5-vinylpyridine (2) andp-toluidine (3), as described, for example, in U.S. Pat. No. 3,409,628(see Example 14):

Compound 1 may be converted to the dimebon analogue 6 having a benzylsubstituent at the pyridoindole 2-position:

Similarly, Kost et al. (J. Gen. Chem. USSR 1960, 30, 2538) describe theuse of 2-methyl-5-vinylpyridine for the preparation of relatedtetrahydrocarbazole structures, such as compound 7:

The synthesis proceeds via 2-methyl-5-(2-phenylaminoethyl)pyridine, ananalogue of compound 1.

The synthesis of dimebon is described by Kost et al. (Chemistry ofHeterocyclic Compounds, 1973, 9, 191). Dimebon, referred to as9-[2-(2′-methyl-5′-pyridyl)ethyl]-3,6-dimethyl-1,2,3,4-tetrahydro-γ-carboline,is prepared by the direct reaction of 2-methyl-5-vinylpyridine with thecarboline (i.e. 3,6-dimethyl-1,2,3,4-tetrahydro-γ-carboline) in thepresence of a very strong base, for example sodium ethoxide.

More recently, Ivachtencko et al. (Bioorg. Med. Chem. Lett., 2009, 19,3183-3187) have synthesised Dimebon and analogues by a similar method,in which the tricyclic ring system (carboline) is formed and reductivelyaminated with 2-methyl-5-vinylpyridine, in the presence of base and aphase transfer catalyst.

However, 2-methyl-5-vinylpyridine is not available commercially, andmust be prepared as required. 2-Methyl-5-vinylpyridine may be obtainedfrom 5-ethyl-2-methylpyridine by oxidation over a heterogeneouscatalyst, typically at elevated temperature. However, the use ofsustained high temperatures means that this method is not suitable forthe large scale production of 2-methyl-5-vinylpyridine.

For example, U.S. Pat. No. 2,611,769 describes the preparation of2-methyl-5-vinylpyridine from 5-ethyl-2-methylpyridine at temperaturesof 600° C. and above. The amount of product obtained is low, around 16%,and requires separation from unreacted starting material.

U.S. Pat. No. 2,716,119 also describes the preparation of2-methyl-5-vinylpyridine from 5-ethyl-2-methylpyridine. The reactionstep is performed at a temperature of around 700° C. and provides around25 to 40% yield of material depending on the heterogeneous catalystchosen.

Furthermore, the preparation of compound I from 2-methyl-5-ethylpyridineis reported as requiring the use of sodium metal (see, for example, U.S.Pat. No. 3,409,628). The use of this flammable/pyrophoric metal makesthis method undesirable for a large scale synthesis.

Given the recently reported benefits of dimebon, there is a need foralternative methods of synthesis that can be reproduced on a large scaleand/or provide increased yields of product. In addition, the methods ofthe invention avoid the need for complex gas phase reactions andpyrophoric reagents. Specialist equipment and procedures are thereforenot needed in the present invention, and the overall cost of thesynthesis may thereby be reduced.

The present inventors have established an alternative route to the keyintermediate that avoids the use of high temperature oxidation andavoids the use of sodium metal.

SUMMARY OF THE INVENTION

The present inventors have now identified certain methods and compoundsfor use in the synthesis of dimebon and its analogues. These methods andcompounds may also find use in the synthesis of intermediates that arethemselves suitable for use in the synthesis of dimebon and itsanalogues.

The methods have certain other properties, for example by comparisonwith the methods of the prior art discussed above.

In other aspects of the invention there are provided compounds offormula (II), (III), (IV), (V), and (VI), and particularly their use inthe synthesis of dimebon or its analogues.

In other aspects there are provided compounds of formula (I), (II),(III), (IV), (V), and (VI) obtained or obtainable by the methodsdescribed herein. In other aspects, the invention pertains to compoundsobtained or obtainable by the methods described herein for use intherapy.

Methods of Synthesis

In a general aspect the present invention provides methods for thesynthesis of a compound of formula (I):

wherein

-R¹ and -R³ are each independently —H or -R^(A);

X is independently selected from CH₂, CHR^(A), CR^(A) ₂, NH, NR^(A), O,S, S(O) and S(O)₂;

-R⁶, -R⁷, -R⁸, and -R⁹ are each independently —H or —P^(A);

-L¹- is independently linear saturated C₁₋₆alkylene;

—P is independently pyridine or phenyl, optionally substituted with oneor more groups —PA;

each -R^(A) is independently:

-   -   -R^(A1), -R^(A2), -R^(A3), -R^(A4), -R^(A5),    -   -L^(A)-R^(A2), -L^(A)-R^(A3), -L^(A)-R^(A4), or -L^(A)-R^(A5);

wherein:

-   -   each -R^(A1) is independently saturated aliphatic C₁₋₆alkyl;    -   each -R^(A2) is independently saturated C₃₋₆cycloalkyl;    -   each -R^(A3) is independently non-aromatic C₃₋₈heterocyclyl;    -   each -R^(A4) is independently C₆₋₁₀carboaryl;    -   each -R^(A5) is independently C₆₋₁₀heteroaryl;    -   each -L^(A)- is independently saturated aliphatic C₁₋₃alkylene;

and wherein:

each C₁₋₆alkyl, C₃₋₆cycloalkyl, non-aromatic C₃₋₈heterocyclyl,C₆₋₁₀carboaryl, C₆₋₁₀heteroaryl, and C₁₋₃alkylene is optionallysubstituted, for example, with one or more substituents;

each —P^(A) is independently selected from:

-   -   -R^(B),    -   —OR^(B), -L^(L)-OR^(B),    -   —F, —Cl, —Br, —I,    -   —CF₃, —OCF₃,    -   —NO₂,    -   —NR^(B) ₂, —NR^(BB)R^(BC),    -   -L^(L)-NR^(B) ₂, -L^(L)-NR^(BB)R^(BC);

and each -L^(L)- is independently saturated aliphatic C₁₋₆alkylene;

-   each -R^(B) is independently:    -   -R^(B1), -R^(B2), -R^(B3), -R^(B4), -R^(B5),    -   -L^(B)-R^(B2), -L^(B)-R^(B3), -L^(B)-R^(B4), or -L^(B)-R^(B5);

wherein:

-   -   each -R^(B1) is independently saturated aliphatic C₁₋₆alkyl;    -   each -R^(B2) is independently saturated C₃₋₆cycloalkyl;    -   each -R^(B3) is independently non-aromatic C₃₋₈heterocyclyl;    -   each -R^(B4) is independently C₆₋₁₀carboaryl;    -   each -R^(B5) is independently C₆₋₁₀heteroaryl;    -   each -L^(B)- is independently saturated aliphatic C₁₋₃alkylene;

-   in each group —NR^(BB)R^(BC), R^(BB) and R^(BC), taken together with    the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or    7-membered non-aromatic ring having exactly 1 ring heteroatom or    exactly 2 ring heteroatoms, wherein one of said exactly 2 ring    heteroatoms is N, and the other of said exactly 2 ring heteroatoms    is independently N or O;

and the dashed line indicates that the bond is a single bond or a doublebond between the 4a and 9a atoms.

In other aspects of the invention there are provided methods for thesynthesis of intermediate compounds for use in the synthesis of compound(I).

The invention also provides the use of the intermediate compounds in thesynthesis of compound (I). The invention also provides the use of theintermediate compounds in the synthesis of other intermediate compounds.

Thus, in one aspect of the invention there are provided methods for thesynthesis of compounds of formula (II):

wherein -R⁶, -R⁷, -R⁸, -R⁹, -L¹-, and —P are as defined according tocompound (I), and -R¹⁹ is independently —H or —P^(A).

Thus, in another aspect of the invention there are provided methods forthe synthesis of compounds of formula (IV):

wherein -L¹- and —P are as defined according to compound (II);

Y is S or O; and

-R^(N1) and -R^(N2) are each independently —H or saturated C₁₋₆alkyl, or-R^(N1) and —R^(N2) taken together with the nitrogen atom to which theyare attached, form a 5-, 6-, or 7-membered non-aromatic ring havingexactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one ofsaid exactly 2 ring heteroatoms is N, and the other of said exactly 2ring heteroatoms is independently N, O, or S.

In another aspect of the invention there are provided methods for thesynthesis of compounds of formula (V):

wherein -L¹- and —P are as defined according to compound (II).

Thus, in another aspect of the invention there are provided methods forthe synthesis of compounds of formula (VI):

wherein -R⁶, -R⁷, -R⁸, -R⁹, -R¹⁰, -L¹-, and —P are as defined accordingto compound (II).

In other aspects of the invention there are provided methods for thesynthesis of compounds of formula (VIII) and (IX):

wherein -R⁶, -R⁷, -R⁸, -R⁹, -R¹⁰, -L¹-, and —P are as defined accordingto compound (II).

Preparation of Compound (II)

In one aspect the present invention provides a method for the synthesisof a compound of formula (II). The method comprises one or more stepsselected from:

(i) the step of converting compound (III) to compound (IV) as describedbelow in Step 1;

(ii) the step of converting compound (IV) to compound (V) as describedbelow in Step 2;

(iii) the step of converting compound (V) to compound (VI) as describedbelow in Step 3; and

(iv) the step of converting compound (VI) to compound (II) as describedbelow in Step 4.

In one embodiment, the method comprises at least step (iv).

In one embodiment, the method comprises at least step (i).

In one embodiment, the method comprises the steps of, in order, (iii)and (iv).

In one embodiment, the method comprises the steps of, in order, (ii),(iii) and (iv).

In one embodiment, the method comprises the steps of, in order, (i),(ii), (iii) and (iv).

In other aspects of the invention, there is provided the use of acompound of formula (III), the use of a compound of formula (IV), theuse of a compound of formula (V), or the use of a compound of formula(VI) in the synthesis of a compound of formula (VI).

Step 1

In one embodiment, the method comprises the step of reacting a compoundof formula (III) to form a compound of formula (IV):

wherein, for compounds of formula (III), —P is as defined according tothe compounds of formula (II) and -T¹ is independently linear saturatedC₁₋₆ alkyl. Compound (IV) is as defined above.

In one embodiment, compound (III) is reacted with an amine,NHR^(N1)R^(N2), and a sulfinating agent to form compound (IV), where-R^(N1) and -R^(N2) are as defined according to the compounds of formula(IV).

In this embodiment, the reaction may be referred to as a Kindlerthionation.

In one embodiment, the product of the reaction is a thioamide i.e. Y isS.

In one embodiment, the product of the reaction is an amide i.e. Y is O.

In one embodiment, the product of the reaction is a mixture of amide andthioamide.

In one embodiment, the thioamide product is obtained where one of-R^(N1) and -R^(N2) is other than —H.

In one embodiment, the amide product is obtained where -R^(N1) and-R^(N2) are each —H.

In one embodiment, the amide product is obtained via the correspondingthioamide.

In one embodiment, the amine has a low boiling point. A reaction mixturecomprising a low boiling amine requires less heat to bring to refluxcompared to a high boiling amine.

In one embodiment, the amine has a boiling point of 130° C. or less.

In one embodiment, the amine has a boiling point of 100° C. or less.

In one embodiment, the amine has a boiling point of 80° C. or less.

In one embodiment, the amine has a boiling point of 60° C. or less.

In one embodiment, the amine has a boiling point of 40° C. or less.

In one embodiment, the reaction mixture is heated to reflux.

In one embodiment, the reaction is performed at a temperature of 10 to170° C.

In one embodiment, the reaction is performed at a temperature of 30 to160° C.

In one embodiment, the reaction is performed at a temperature of 10 to140° C.

In one embodiment, the reaction is performed at a temperature of 30 to140° C.

In one embodiment, the reaction is performed at a temperature of 30 to80° C.

In one embodiment, the reaction is performed at a temperature of 30 to60° C.

In one embodiment, the reaction is performed for a time of at least 5hours.

In one embodiment, the reaction is performed for a time of at least 10hours.

In one embodiment, the reaction is performed for a time of at least 15hours.

In one embodiment, the reaction is performed for a time of about 16hours.

In one embodiment, the reaction is performed in a sealed reactionvessel.

In one embodiment, the reaction is performed in the presence of atertiary amine base.

In one embodiment, the tertiary amine base is pyridine.

In one embodiment, compound (III) is independently5-acetyl-2-methylpyridine.

In one embodiment, NHR^(N1)R^(N2) is independently morpholine. In thisembodiment, compound (IV) is 6-methyl-3-pyridylthioacetmorpholide.

In one embodiment, NHR^(N1)R^(N2) is independently diethylamine. In thisembodiment, compound (IV) isN,N-diethyl-2-(6-methyl-pyridin-3-yl)-thioacetamide.

In one embodiment, NHR^(N1)R^(N2) is independently ammonia. In thisembodiment, compound (IV) is 2-(6-methyl-pyridin-3-yl)-acetamide.

In one embodiment, the sulfinating agent is, or comprises, sulfur.

In one embodiment, the sulfinating agent is sulfur.

In one embodiment, the sulfinating agent is, or comprises, a polysulfidesalt.

In one embodiment, the sulfinating agent is a polysulfide salt.

In one embodiment, the polysulfide salt is ammonium polysulfide.

In one embodiment, the step of reacting 5-acetyl-2-methylpyridine toform 6-methyl-3-pyridylthioacetmorpholide is performed as described inSperber et al., which is incorporated by reference herein. Inparticular, the intermediates in the synthesis of ethyl6-methyl-3-pyridylacetate are referred to, as described in Table 1 andpages 708-709.

Step 2

In one embodiment, the method comprises the step of reacting a compoundof formula (IV) to form a compound of formula (V):

wherein compounds (IV) and (V) are as defined above. The reaction may bereferred to as the hydrolysis of the thioamide or amide, as appropriate.

In one embodiment, the hydrolysis is by reaction with a base.

In one embodiment, the base is or comprises a hydroxide salt.

In one embodiment, the base is or comprises an alkali metal hydroxide.

In one embodiment, the base is or comprises sodium or lithium hydroxide.

In one embodiment, the base is sodium hydroxide.

In one embodiment, the base is an aqueous base.

In one embodiment, the molar ratio of base to compound (IV) is from 2.0to 4.0.

In one embodiment, the range is 2.5 to 3.5.

In one embodiment, the ratio is about 3.3.

In one embodiment, the base is used in an amount of from 2.0 to 4.0molar equivalents, relative to the amount of compound (IV).

In one embodiment, the base is used in an amount of from 2.5 to 3.5molar equivalents, relative to the amount of compound (IV).

In one embodiment, the base is used in an amount of about 3.3 molarequivalents, relative to the amount of compound (IV).

In one embodiment, the reaction is performed in an aqueous medium.

In one embodiment, the aqueous medium comprises a saturated aliphaticC₁₋₆ alkyl alcohol.

In one embodiment, the aqueous medium comprises methanol, ethanol oriso-propyl alcohol.

In one embodiment, the aqueous medium comprises ethanol.

In one embodiment, the reaction is performed at reflux.

In one embodiment, the reaction is performed at a temperature of 10 to100° C.

In one embodiment, the reaction is performed at a temperature of 30 to90° C.

In one embodiment, the reaction is performed at a temperature of 50 to85° C.

In one embodiment, the reaction is performed for a time of at least 5hours.

In one embodiment, the reaction is performed for a time of at least 10hours.

In one embodiment, the reaction is performed for a time of at least 15hours.

In one embodiment, the reaction is performed for a time of about 16hours.

In one embodiment, the reaction is stirred during the reaction step.

In one embodiment, after reaction, the aqueous medium is concentrated.

In one embodiment, after reaction, the aqueous medium is concentrated byremoval of the saturated aliphatic C₁₋₆ alkyl alcohol, where present.

In one embodiment, after reaction, the aqueous medium is neutralised.

In one embodiment, after reaction, the pH of the aqueous medium isadjusted to lower pH.

In one embodiment, the lower pH is 6-8.

In one embodiment, the lower pH is about 7.

In one embodiment, the lower pH is 7.0.

In one embodiment, the pH of the aqueous medium is adjusted with aqueousacid.

In one embodiment, the pH of the aqueous medium is adjusted with aqueoushydrochloric acid.

In one embodiment, after reaction, the pH of the aqueous medium isadjusted after the aqueous medium is concentrated.

In one embodiment, after reaction, the aqueous medium is removed. Theproduct is retained in the remaining mixture.

In one embodiment, after reaction, the aqueous medium is removed afterthe pH of the aqueous medium is adjusted.

In one embodiment, after the aqueous medium is removed, the remainingmixture is slurried in solvent.

In one embodiment, the solvent is or comprises a saturated aliphaticC₁₋₆ alkyl alcohol.

In one embodiment, the solvent is or comprises methanol, ethanol oriso-propyl alcohol.

In one embodiment, the solvent is methanol.

In one embodiment, the solvent is hot.

In one embodiment, the solvent is at a temperature of 20 to 60° C.

In one embodiment, the solvent is at a temperature of 30 to 55° C.

In one embodiment, the solvent is at a temperature of 40 to 50° C.

In one embodiment, after the remaining mixture is slurried in solvent,the slurry is filtered, and the filtrate collected.

In one embodiment, the slurry is filtered hot.

In one embodiment, the slurry is at a temperature of 20 to 60° C.

In one embodiment, the slurry is at a temperature of 30 to 55° C.

In one embodiment, the slurry is at a temperature of 40 to 50° C.

In one embodiment, after filtration, the filtrate is concentrated.

In one embodiment, after filtration, the filtrate is purified bychromatography.

In one embodiment, the filtrate is concentrated filtrate.

In one embodiment, the chromatography is flash column chromatography.

In one embodiment, the eluant in the chromatography is a mixture ofethyl acetate and methanol.

In one embodiment, the eluant is a 9:1 mixture of ethyl acetate andmethanol.

Hydrolysis of compound (IV) produces an amine, NHR^(N1)R^(N2), as areaction by-product, where and -R^(N1) and -R^(N2) are as defined forcompound (IV).

In one embodiment, after reaction, the amine by-product is separatedfrom compound (V).

The amine by-product may be separated from compound (V) duringconcentration of the aqueous medium, or subsequently duringconcentration of the filtrate.

In one embodiment, the amine by-product is a low boiling amine.

In one embodiment, the amine by-product has a boiling point of 100° C.or less.

In one embodiment, the amine by-product has a boiling point of 80° C. orless.

In one embodiment, the amine by-product has a boiling point of 60° C. orless.

In one embodiment, the amine by-product has a boiling point of 40° C. orless.

In one embodiment, the amine by-product is separated from compound (V)by distillation, which includes concentration in vacuo.

Where the amine by-product is a high boiling amine, the separation ofthe by-product from compound (V) may be difficult by concentrationalone. In one embodiment, a high boiling amine by-product is separatedfrom compound (V) by chromatography, or distillation and chromatography.

In one embodiment, after reaction, the amine by-product is separatedfrom the aqueous medium by washing with an organic solvent.

In one embodiment, after reaction, the aqueous medium is washed with anorganic solvent.

In one embodiment, after reaction, the aqueous medium is washed with anorganic solvent after concentration of the aqueous medium.

In one embodiment, the aqueous medium is washed once, twice, or threetimes with the organic solvent.

In one embodiment, the aqueous medium is washed three times with theorganic solvent.

In one embodiment, the organic solvent is dichloromethane (DCM).

In one embodiment, the amine by-product is diethylamine.

In one embodiment, the amine by-product is ammonia.

In one embodiment, the amine by-product is morpholine.

In one embodiment, compound (IV) is independently6-methyl-3-pyridylthioacetmorpholide.

In one embodiment, compound (IV) is independentlyN,N-diethyl-2-(6-methyl-pyridin-3-yl)-thioacetamide.

In one embodiment, compound (IV) is independently2-(6-methyl-pyridin-3-yl)-acetamide

In one embodiment, compound (V) is independently6-methyl-3-pyridineacetic acid.

In one embodiment, the step of reacting6-methyl-3-pyridylthioacetmorpholide to form 6-methyl-3-pyridineaceticacid is performed as described in Sperber et al., which is incorporatedby reference herein. In particular, the intermediates in the synthesisof ethyl 6-methyl-3-pyridylacetate are referred to, as described inTable 1 and pages 708-709.

Step 3

In one embodiment, the method comprises the step of reacting a compoundof formula (V) to form a compound of formula (VI):

wherein compounds (V) and (VI) are as defined above.

In one embodiment, compound (V) is reacted with a compound of formula(VII) to form compound (VI):

wherein -R⁶, -R⁷, -R⁸, -R⁹, and -R¹⁹ are as defined according to thecompounds of formula (II).

The reaction may be referred to as the coupling of compounds (V) and(VII).

In one embodiment, the molar ratio of compound (V) to compound (VII) is1.0 to 3.0.

In one embodiment, the molar ratio of compound (V) to compound (VII) is1.1 to 2.0.

In one embodiment, the ratio is about 1.5.

In one embodiment, the amine compound (VII) is used in an amount of from1.0 to 3.0 molar equivalents, relative to the amount of carboxylic acidcompound (V).

In one embodiment, the amine compound (VII) is used in an amount of from1.1 to 2.0 molar equivalents, relative to the amount of carboxylic acidcompound (V).

In one embodiment, the amine compound (VII) is used in an amount ofabout 1.5 molar equivalents, relative to the amount of carboxylic acidcompound (V).

In one embodiment, the reaction is performed in an organic medium.

In one embodiment, the organic medium is or comprises an ether solvent.

In one embodiment, the ether solvent is tetrahydrofuran (THF).

In one embodiment, the organic medium is or comprises DCM.

In one embodiment, the organic medium is or comprises dimethylformamide(DMF).

In one embodiment, the organic medium is anhydrous DMF.

In one embodiment, the reaction is performed in the presence of a phasetransfer catalyst (PTC).

Phase transfer catalysts are known in the art, and include quaternaryammonium salts and phosphonium salts. Examples of ammonium saltsinclude, but are not limited to, tetraalkylammonium salts (e.g. Bu₄NI,Bu₄NBF₄, Bu₄NBr, Bu₄NF), quaternary pyridinium salts, and other phasetransfer agents commonly used in the domestic chemicals market, such ascetyl trimethylammonium bromide, cocamidopropyl betaine. Examples ofphosphonium salts include, but are not limited to alkyl and arylphosphonium halides (e.g. tetraphenyl phosphonium bromide, methyltriphenyl phosphonium bromide, butyl triphenyl phosphonium chloride,tetradecyl(trihexyl)phosphonium chloride,tetradecyl(trihexyl)phosphonium bromide).

Other phase transfer catalysts of use in the methods of the inventioninclude those discussed in Aldrichimica Acta, 1976, volume 9, issue 3and in the chapter on PTC in “Industrial Catalysis” by Jens Hagen(Wiley-VCH, 2006), which are each incorporated herein by reference.

In one embodiment the PTC is used in an amount of from 5 to 25 mol %,relative to the amount of compound (V).

In one embodiment the PTC is used in an amount of from 5 to 15 mol %,relative to the amount of compound (V).

In one embodiment the PTC is used in an amount of about 10 mol %,relative to the amount of compound (V).

In one embodiment the PTC is Bu₄NI.

In one embodiment the PTC is Bu₄NBF₄.

In one embodiment, the reaction, is performed under an inert atmosphere.

In one embodiment, the reaction is performed under an argon or nitrogenatmosphere.

In one embodiment, the reaction is stirred during the reaction step.

In one embodiment, compound (V) is coupled to compound (VII) using oneor more coupling reagents.

In one embodiment, compound (V) is coupled to compound (VII) using acoupling reagent.

In one embodiment, the coupling reagent is a carbodiimide.

In one embodiment, the coupling reagent is a haloformate.

In one embodiment, the coupling reagent is or compriseshydroxybenzotriazole

(HOBt), dimethylaminopyridine (DMAP),benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP), 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT),2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), O-Benzotriazole-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU),2-(6-chloro-1-H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate (HCTU), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBroP), orN,N,N′,N′-tetramethyl-O-(benzotriazol-1-Muronium tetrafluoroborate(TBTU).

Other coupling reagents suitable for use in the reaction include thosecondensation reagents described in the Novabiochem Catalog 2006/2007,and in particular at pages 337-347 and Sections 3.1-3.2.

In one embodiment, the coupling reagent is added before compound (VII)is added.

In one embodiment, the coupling reagent is added after compound (VII) isadded.

In one embodiment, the coupling reagent is added at the same time ascompound (VII) is added.

In one embodiment, the molar ratio of compound (V) to the couplingreagent is 1.0 to 2.0.

In one embodiment, the molar ratio of compound (V) to the couplingreagent is 1.0 to 1.5.

In one embodiment, the ratio is about 1.1.

In one embodiment, the coupling reagent is used in an amount of from 1.0to 3.0 molar equivalents, relative to the amount of carboxylic acidcompound (V).

In one embodiment, the coupling reagent is used in an amount of from 1.5to 2.5 molar equivalents, relative to the amount of carboxylic acidcompound (V).

In one embodiment, the coupling reagent is used in an amount of about2.0 molar equivalents, relative to the amount of carboxylic acidcompound (V).

In one embodiment, the coupling reagent is used in an amount of from 1.0to 1.5 molar equivalents, relative to the amount of carboxylic acidcompound (V).

In one embodiment, the coupling reagent is used in an amount of about1.1 molar equivalents, relative to the amount of carboxylic acidcompound (V).

In one embodiment, the coupling reagent is used in combination with abase.

In one embodiment, the base is an organic base.

In one embodiment, the organic base is an amine base.

In one embodiment, the amine base is triethylamine,di-iso-propylethylamine or N-methylmorpholine.

In one embodiment, the molar ratio of compound (V) to the base is 1.0 to2.0.

In one embodiment, the molar ratio of compound (V) to the couplingreagent is 1.0 to 1.2.

In one embodiment, the ratio is about 1.0.

In one embodiment, the base is used in an amount of from 1.0 to 2.0molar equivalents, relative to the amount of carboxylic acid compound(V).

In one embodiment, the base is used in an amount of from 1.0 to 2.0molar equivalents, relative to the amount of carboxylic acid compound(V).

In one embodiment, the base is used in an amount of about 1.0 molarequivalents, relative to the amount of carboxylic acid compound (V).

In one embodiment, after filtration, the filtrate is purified bychromatography.

In one embodiment, the chromatography is flash column chromatography.

In one embodiment, the eluant in the chromatography is or comprisesethyl acetate.

Carbodiimide Coupling Reaction:

In one embodiment, the coupling reagent is a carbodiimide.

In one embodiment, the carbodiimide is N,N′-dicyclohexylcarbodiimide(DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), orN,N′-diisopropylcarbodiimide DIC.

In one embodiment, the carbodiimide is used in combination with one ormore of HOBt, DMAP, PyBOP, MSNT, HATU, HBTU, HCTU, PyBroP, or TBTU.

In one embodiment, the reaction is performed at room temperature.

In one embodiment, the reaction is performed at a temperature of 10 to30° C.

In one embodiment, the reaction is performed at a temperature of 15 to25° C.

In one embodiment, the reaction is performed for a time of 2 to 12hours.

In one embodiment, the reaction is performed for a time of 4 to 10hours.

In one embodiment, the reaction is performed for about 6 hours.

In one embodiment, after reaction, the organic medium is filtered, andthe filtrate collected.

In one embodiment, after filtration, the filtrate is concentrated.

In one embodiment, after filtration, the filtrate is purified bychromatography.

In one embodiment, the filtrate is a concentrated filtrate.

In one embodiment, the chromatography is flash column chromatography.

In one embodiment, the eluant in the chromatography is or comprisesethyl acetate.

Mixed Anhydride Coupling reaction:

In one embodiment, the coupling reagent is a haloformate.

In one embodiment, the haloformate is a C₁₋₆ alkyl haloformate.

In one embodiment, the haloformate is butyl chloroformate.

In one embodiment, the haloformate is iso-butyl chloroformate.

In one embodiment, the reaction is performed for a time of 2 to 24hours.

In one embodiment, the reaction is performed for a time of 4 to 18hours.

In one embodiment, the reaction is performed for about 16 hours.

In one embodiment, the reaction is performed at room temperature orless.

In one embodiment, the room temperature is 25° C.

In one embodiment, the room temperature is a temperature of 10 to 30° C.

In one embodiment, the room temperature is a temperature of 15 to 25° C.

In one embodiment, the coupling reagent is added to compound (V) at atemperature less than room temperature.

In one embodiment, less than room temperature is 0° C. or less.

In one embodiment, less than room temperature is −10° C. or less.

In one embodiment, less than room temperature is −78° C.

In one embodiment, after the coupling reagent is added to compound (V)at a temperature less than room temperature, the reaction is allowed towarm to room temperature.

In one embodiment, the reaction is held at a temperature less than roomtemperature for at most 60 min, and then allowed to warm to roomtemperature.

In one embodiment, the reaction is held at a temperature less than roomtemperature for at most 30 min.

In one embodiment, the reaction is cooled using a −78° C. coolant bath.

In one embodiment, the reaction is cooled, to produce an internaltemperature of the reaction mixture of between −50° C. and -25° C.

In one embodiment, the reaction is cooled to produce an internaltemperature of the reaction mixture of between −45° C. and -35° C.

In one embodiment, the reaction is cooled to produce an internaltemperature of the reaction mixture of about −40° C.

Step 4

In one embodiment, the method comprises the step of reacting a compoundof formula (VI) to form a compound of formula (II):

wherein compounds (VI) and (II) are as defined above. The reaction maybe referred to as the reduction of the amide.

In one embodiment, compound (VI) is reacted with a reducing agent toform compound (II).

In one embodiment, the reducing agent is, or comprises, LiAlH₄.

In one embodiment, the reducing agent is LiAlH₄.

In one embodiment, the reducing agent is, or comprises, a boranereducing agent.

In one embodiment, the reducing agent is a borane reducing agent.

In one embodiment, the borane reducing agent is BH₃ or a C₃₋₁₀ dialkylborane.

In one embodiment, the C₃₋₁₀ dialkyl borane is9-borabicyclo(3.3.1)nonane (9-BBN) or bis-3-methyl-2-butylborane.

In one embodiment, the reducing agent is, or comprises, a borohydride.

In one embodiment, the borohydride is Bu₄NBH₄.

In one embodiment, the molar ratio of compound (VI) to the reducingreagent is 1.0 to 10.0.

In one embodiment, the molar ratio of compound (VI) to the reducingreagent is 2.0 to 7.5.

In one embodiment, the ratio is about 5.0.

In one embodiment, the reducing agent is used in an amount of from 1.0to 10.0 molar equivalents, relative to the amount of compound (VI).

In one embodiment, the reducing agent is used in an amount of from 2.0to 7.5 molar equivalents, relative to the amount of compound (VI).

In one embodiment, the reducing agent is used in an amount of about 5.0molar equivalents, relative to the amount of compound (VI).

In one embodiment, the reducing agent is used in an amount of about 3.0molar equivalents, relative to the amount of compound (VI).

In one embodiment, the reaction is performed in an organic medium.

In one embodiment, the organic medium is or comprises an ether solvent.

In one embodiment, the ether solvent is THF.

In one embodiment, the organic medium is DCM.

In one embodiment, the concentration of compound (VI) in the organicmedium is at least 0.1 M.

In one embodiment, the concentration of compound (VI) in the organicmedium is at least 0.2 M.

In one embodiment, the concentration of compound (VI) in the organicmedium is at least 0.4 M.

In one embodiment, the concentration of compound (VI) in the organicmedium is about 0.4 M.

In one embodiment, the reaction is performed at reflux.

In one embodiment, the reaction is performed at a temperature of 10 to100° C.

In one embodiment, the reaction is performed at a temperature of 30 to90° C.

In one embodiment, the reaction is performed at a temperature of 50 to85° C.

In one embodiment, the reaction is performed for 5 to 40 hours.

In one embodiment, the reaction is performed for 10 to 20 hours.

In one embodiment, the reaction is performed for 20 hours at most.

In one embodiment, the reaction is performed for a time of about 16hours.

In one embodiment, the reaction is stirred during the reaction step.

In one embodiment, the reducing reagent is added to compound (VI) at atemperature less than room temperature.

In one embodiment, less than room temperature is 0° C. or less.

In one embodiment, less than room temperature is −10° C. or less.

In one embodiment, less than room temperature is −78° C.

In one embodiment, less than room temperature is about 0° C.

In one embodiment, after the reducing reagent is added to compound (VI)at a temperature less than room temperature, the reaction is allowed towarm to room temperature.

In one embodiment, the reaction is held at a temperature less than roomtemperature for at most 30 min, and then allowed to warm to roomtemperature.

In one embodiment, the reaction is held at a temperature less than roomtemperature for at most 10 min.

In one embodiment, the reducing reagent is added to compound (VI)portionwise until no further gas evolution is observed. Thereafter theremaining reducing agent may be added in one portion.

In one embodiment, the reaction is terminated by the addition of wetorganic solvent.

In one embodiment, the organic solvent is an ether solvent.

In one embodiment, the ether solvent is THF.

In one embodiment, the wet organic solvent is added until no further gasevolution is observed.

In one embodiment, after reaction, the reaction mixture is concentrated.

In one embodiment, after reaction, the reaction mixture is concentratedto remove the organic solvent.

In one embodiment, after reaction, the reaction mixture is hydrolysed.

In one embodiment, after reaction, the reaction mixture is hydrolysed byboiling in aqueous acid.

In one embodiment, the aqueous acid is aqueous hydrochloric acidsolution.

In one embodiment, the aqueous hydrochloric acid solution is at aconcentration of 0.5M to 2.0M.

In one embodiment, the hydrochloric acid solution is at a concentrationof about 1.0M.

In one embodiment the hydrolysis is performed for 10 to 60 minutes.

In one embodiment the hydrolysis is performed for about 30 minutes.

In one embodiment the hydrolysis is performed after the reaction mixtureis concentrated.

In one embodiment, after reaction, the reaction mixture is filtered, andthe filtrate collected.

In one embodiment, the collected solids are washed with organic solvent.The washings are combined with the collected filtrate.

In one embodiment, the organic solvent is an ether solvent as describeabove.

In one embodiment, after filtration, the filtrate is dried with a dryingagent.

In one embodiment, the drying agent is magnesium sulfate or sodiumsulfate.

In one embodiment, after filtration, the organic medium is removed e.g.in vacuo. The product is retained in the remaining mixture.

In one embodiment, after filtration, the filtrate is purified bychromatography.

In one embodiment, the filtrate is concentrated filtrate.

In one embodiment, the chromatography is flash column chromatography.

In one embodiment, the eluant in the chromatography is a mixture ofethyl acetate and petrol.

In one embodiment, the eluant is a 1:1 mixture of ethyl acetate andpetrol.

In one embodiment, the eluant is a 1:1 mixture of ethyl acetate andpetrol (40-60).

Preferred Synthesis

In one embodiment, the compound of formula (II) is[2-(6-methyl-pyridin-3-yl)-ethyl]-p-tolyl-amine 1) and is prepared from3-acetyl-6-methylpyridine as shown in scheme 1.

In an alternative embodiment,N,N-diethyl-2-(6-methyl-pyridin-3-yl)-thioacetamide (10) is used inplace of 6-methyl-3-pyridylthioacetmorpholide (9) in the scheme above.

In an alternative embodiment, 2-(6-methyl-pyridin-3-yl)-acetamide (14)is used in place of 6-methyl-3-pyridylthioacetmorpholide (9) in thescheme above.

Preparation of Compound (VI)

In one aspect the present invention provides a method for the synthesisof a compound of formula (VI). The method comprises one or more stepsselected from:

(i) the step of converting a compound of formula (III) to compound (IV)as described above in Step 1;

(ii) the step of converting a compound of formula (IV) to compound (V)as described above in Step 2; and

(iii) the step of converting a compound of formula (V) to compound (VI)as described above in Step 3.

In one embodiment, the method comprises at least step (iii).

In one embodiment, the method comprises the steps of, in order, (ii) and(iii).

In one embodiment, the method comprises the steps of, in order, (i),(ii) and (iii).

In other aspects of the invention, there is provided the use of acompound of formula (III), the use of a compound of formula (IV), or theuse of a compound of formula (V) in the synthesis of a compound offormula (VI).

Preparation of Compound (V)

In one aspect the present invention provides a method for the synthesisof a compound of formula (V). The method comprises one or more stepsselected from:

(i) the step of converting a compound of formula (III) to compound (IV)as described above in Step 1; and

(ii) the step of converting a compound of formula (IV) to compound (V)as described above in Step 2.

In one embodiment, the method comprises at least step (i).

In one embodiment, the method comprises the steps of, in order, (i) and(ii).

In other aspects of the invention, there is provided the use of acompound of formula (III) or the use of a compound of formula (IV) inthe synthesis of a compound of formula (V).

Preparation of Compound (IV)

In one aspect the present invention provides a method for the synthesisof a compound of formula (IV). The method comprises the step ofconverting a compound of formula (III) to compound (IV) as describedabove in Step 1.

In another aspect of the invention, there is provided the use of acompound of formula (III) in the synthesis of a compound of formula(IV).

Preparation of Compounds (VIII) and (IX)

In one aspect the present invention provides a method for the synthesisof a compound of formula (VIII).

The method comprises one or more steps selected from:

(i) the step of converting a compound of formula (III) to compound (IV)as described above in Step 1;

(ii) the step of converting a compound of formula (IV) to compound (V)as described above in Step 2;

(iii) the step of converting a compound of formula (V) to compound (VI)as described above in Step 3;

(iv) the step of converting compound (VI) to compound (II) as describedabove in Step 4; and optionally the step of:

(vi) converting compound (II) to compound (VIII).

Step (vi) may be referred to as a nitration reaction. In one embodiment,the nitration is by reaction with a nitrous acid. Compound (II) may beconverted to compound (VIII) by the methods described in U.S. Pat. No.3,409,628. See, for example, the synthesis of2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine as described inExample 14. Alternative procedures will be familiar to those of skill inthe art.

In one embodiment, compound (VIII) is2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine.

In one embodiment, the method comprises at least step (iv).

In one embodiment, the method comprises the steps of, in order, at leaststep (iv) and (vi).

In one embodiment, the method comprises the steps of, in order, at leaststep (i) and (vi).

In one embodiment, the method comprises the steps of, in order, (iii)and (iv).

In one embodiment, the method comprises the steps of, in order, (iii),(iv) and (vi).

In one embodiment, the method comprises the steps of, in order, (ii),(iii) and (iv).

In one embodiment, the method comprises the steps of, in order, (ii),(iii), (iv) and (vi).

In one embodiment, the method comprises the steps of, in order, (i),(ii), (iii) and (iv).

In one embodiment, the method comprises the steps of, in order, (i),(ii), (iii), (iv) and (vi).

In one aspect the present invention provides a method for the synthesisof a compound of formula (IX).

The method comprises one or more steps selected from:

(i) the step of converting a compound of formula (III) to compound (IV)as described above in Step 1;

(ii) the step of converting a compound of formula (IV) to compound (V)as described above in Step 2;

(iii) the step of converting a compound of formula (V) to compound (VI)as described above in Step 3;

(iv) the step of converting compound (VI) to compound (II) as describedabove in Step 4;

and optionally comprises one or both the steps of:

(vi) converting compound (II) to compound (VIII) as described above; and

(vii) converting compound (VIII) to compound (IX).

Step (vii) may be referred to as a reduction reaction. In oneembodiment, the reduction is by reaction with zinc in the presence ofacid. Compound (VIII) may be converted to compound (IX) by the methodsdescribed in U.S. Pat. No. 3,409,628. See, for example, the synthesis of2-methyl-5-(N-amino-2-p-tolylaminoethyl)pyridine as described in Example14. Alternative procedures will be familiar to those of skill in theart.

In one embodiment, the method comprises at least step (iv).

In one embodiment, the method comprises the steps of, in order, at leaststep (iv) and (vii).

In one embodiment, the method comprises the steps of, in order, at leaststep (iv), (vi) and (vii)

In one embodiment, the method comprises the steps of, in order, at leaststep (i) and (vii).

In one embodiment, the method comprises the steps of, in order, (iii)and (iv).

In one embodiment, the method comprises the steps of, in order, (iii),(iv) and (vii).

In one embodiment, the method comprises the steps of, in order, (ii),(iii) and (iv).

In one embodiment, the method comprises the steps of, in order, (ii),(iii), (iv) and (vii).

In one embodiment, the method comprises the steps of, in order, (i),(ii), (iii) and (iv).

In one embodiment, the method comprises the steps of, in order, (i),(ii), (iii), (iv) and (vii).

In one embodiment, the method comprises the steps of, in order, (i),(ii), (iii), (iv), (vi) and (vii).

In one embodiment, compound (IX) is2-methyl-5-(N-amino-2-p-tolylaminoethyl)pyridine.

Preparation of Compound (I)

In one aspect of the invention, there is provided a method for thesynthesis of compound (I).

In one embodiment, the method comprises one or more of steps 1-4 asdescribed above in relation to compound (I), and optionally may furthercomprise step 5, as described below. In this embodiment, in steps 3, 4and 5, -R¹⁰ is —H.

In one aspect the present invention provides a method for the synthesisof a compound of formula (II). The method comprises one or more stepsselected from:

(i) the step of converting compound (III) to compound (IV) as describedabove in Step 1;

(ii) the step of converting compound (IV) to compound (V) as describedabove in Step 2;

(iii) the step of converting compound (V) to compound (VI) as describedabove in Step 3;

(iv) the step of converting compound (VI) to compound (II) as describedabove in Step 4; and optionally

(v) converting compound (II) to compound (I) as described below in Step5.

In one embodiment, the method comprises at least step (iv).

In one embodiment, the method comprises the steps of, in order, at leaststep (iv) and (v).

In one embodiment, the method comprises the steps of, in order, at leaststep (i) and (v).

In one embodiment, the method comprises the steps of, in order, (iii)and (iv).

In one embodiment, the method comprises the steps of, in order, (iii),(iv) and (v).

In one embodiment, the method comprises the steps of, in order, (ii),(iii) and (iv).

In one embodiment, the method comprises the steps of, in order, (ii),(iii), (iv) and (v).

In one embodiment, the method comprises the steps of, in order, (i),(ii), (iii) and (iv).

In one embodiment, the method comprises the steps of, in order, (i),(ii), (iii), (iv) and (v).

Step 5

In one embodiment, the method further comprises the step of converting acompound of formula (II) to a compound of formula (VIII). The reactionmay be referred to as a nitration reaction. In one embodiment, thenitration is by reaction with a nitrous acid. Compound (II) may beconverted to compound (VIII) by the methods described in U.S. Pat. No.3,409,628. See, for example, the synthesis of2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine as described inExample 14.

In one embodiment, the method further comprises the step of converting acompound of formula (VIII) to a compound of formula (IX). The reactionmay be referred to as a reduction reaction. In one embodiment, thereduction is by reaction with a reducing agent.

In one embodiment, the reduction is by reaction with LiAlH₄.

In one embodiment, the reduction is by reaction with LiAlH₄ in an ethersolvent.

In one embodiment, the ether solvent is THF.

In one embodiment, the reduction is by reaction with zinc.

In one embodiment, the reduction is by reaction with zinc in thepresence of acid.

In some embodiment, the use of LiAlH₄ over zinc is preferred. On a smallscale, the use of zinc in the presence of acid was found to over reducethe substrate to yield the compound of formula (II). The combination ofLiAlH₄ in THF was found to give compound (IX) in good yield.

Compound (VIII) may be converted to compound (IX) by the methodsdescribed in U.S. Pat. No. 3,409,628. See, for example, the synthesis of2-methyl-5-(N-amino-2-p-tolylaminoethyl)pyridine as described in Example14.

In one embodiment, method further comprises the steps of, in order,converting a compound of formula (II) to a compound of formula (VIII),and converting a compound of formula (VIII) to a compound of formula(IX).

In one embodiment, the method further comprises the steps of convertinga compound of formula (IX) to a compound of formula (I). The reactionmay be referred to as a condensation reaction. In one embodiment, thecondensation is by reaction with compound (X).

In one embodiment, the method comprises the step of reacting a compoundof formula (IX) to form a compound of formula (I).

In one embodiment, the reaction is performed in an organic medium.

In one embodiment, the reaction is performed at reflux.

In one embodiment, the reaction is performed at a temperature of 10 to100° C.

In one embodiment, the reaction is performed at a temperature of 30 to90° C.

In one embodiment, the reaction is performed at a temperature of 50 to85° C.

Compound (IX) may be converted to compound (I) by the methods describedin U.S. Pat. No. 3,409,628. See, for example, the synthesis of2-benzyl-8-methyl-1,3,4,5-tetrahydro-5-[2-(6-methyl-3-pyridyl)ethyl]12H-pyridol[4,3-b]indoleas described in Example 14.

In one embodiment, method further comprises the steps of, in order,converting a compound of formula (II) to a compound of formula (VIII);converting a compound of formula (VIII) to a compound of formula (IX);and converting a compound of formula (IX) to a compound of formula (I).

In one embodiment, compound (I) is prepared from compound (II) in amethod as described in U.S. Pat. No. 3,409,628, which is incorporated byreference herein. Example methods include Example 14 of that document.

In one embodiment, compound (II) is converted in three steps to compound(I), as shown in Scheme 2.

wherein, for compounds (VIII), (IX) and (X), -R¹, -R³, -R⁶, -R⁷, -R⁸,-R⁹, X, -L¹-, and —P, are as defined according to compound (II), and-R¹⁰ is —H.

In one embodiment, compound (I) is dimebon(9-[2-(2′-methyl-5′-pyridyl)ethyl]-3,6-dimethyl-1,2,3,4-tetrahydro-γ-carboline).

In one embodiment, compound (I) is8-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-1,3,4,5-tetrahydro-pyrano[4,3-b]indole(15).

In one embodiment, compound (I) is8-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-1,3,4,5-tetrahydro-thiopyrano[4,3-b]indole(16).

In one embodiment, compound (II) is2-(6-methyl-pyridin-3-yl)-N-p-tolyl-acetamide.

In one embodiment, compound (VIII) is2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine.

In one embodiment, compound (IX) is2-methyl-5-(N-amino-2-p-tolylaminoethyl)pyridine.

In one embodiment, compound (X) is 1-methyl-piperidone-4(1-methyl-piperidin-4-one).

In one embodiment, compound (X) is tetrahydro-pyran-4-one.

In one embodiment, compound (X) is tetrahydro-thiopyran-4-one.

Use of Compounds as Intermediates

In a general aspect the present invention provides the use of variouscompounds described herein in the synthesis of other compounds describedherein.

Thus, in one aspect, there is provided the use of compound (III) in thesynthesis of compound (I) or compound (II).

In another aspect, there is provided the use of compound (IV) in thesynthesis of compound (I) or compound (II).

In another aspect, there is provided the use of compound (V) in thesynthesis of compound (I) or compound (II).

In another aspect, there is provided the use of compound (VI) in thesynthesis of compound (I) or compound (II).

Compounds (III), (IV), (V) and (VI) may be referred to as intermediatesin a synthesis of compound (I) or compound (II).

Compounds

In other aspects, the present invention provides compounds of formula(I), (II), (III), (IV), (V), and (VI) as described herein.

In one embodiment, the compound is a compound of formula (VI).

In one embodiment, the compound is a compound of formula (II).

In one embodiment, the compound is a compound of formula (III).

In one embodiment, the compound is a compound of formula (IV).

In one embodiment; the compound is a compound of formula (V).

In one embodiment, the compound is a compound of formula (I).

Embodiments

Various embodiments of the invention are described in detail below.

Preferred Compounds

In one embodiment, the compound of formula (I) is a compound of formula:

In one embodiment, the compound of formula (I) is a compound of formula:

In one embodiment, the compound of formula (I) is dimebon.

In one embodiment, the compound is a compound of formula (I) wherein Xis selected from O, S, S(O) and S(O)₂.

In one embodiment, the compound of formula (I) is8-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-1,3,4,5-tetrahydro-pyrano[4,3-b]indole.

In one embodiment, the compound of formula (I) is8-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-1,3,4,5-tetrahydro-thiopyrano[4,3-b]indole.

In one embodiment, the compound of formula (II) is a compound offormula:

In one embodiment, the compound of formula (II) is a compound offormula:

In one embodiment, the compound of formula (II) is:

Compound Structure and Name 1

In one embodiment, the compound of formula (III) is a compound offormula:

In one embodiment, the compound of formula (III) is a compound offormula:

In one embodiment, the compound of formula (III) is:

Compound Structure and Name 8

In one embodiment, the compound of formula (IV) is a compound offormula:

In one embodiment, the compound of formula (IV) is a compound offormula:

In one embodiment, the compound of formula (IV) is a compound offormula:

In one embodiment, the compound of formula (IV) is a compound offormula:

In one embodiment, the compound of formula (IV) is selected from:

Compound Structure and Name  9

10

14

In one embodiment, the compound of formula (V) is a compound of formula:

In one embodiment, the compound of formula (V) is a compound of formula:

In one embodiment, the compound of formula (V) is:

Compound Structure and Name 11

In one embodiment, the compound of formula (VI) is a compound offormula:

In one embodiment, the compound of formula (VI) is a compound offormula:

In one embodiment, the compound of formula (VI) is:

Compound Structure and Name 12

In one embodiment, the compound of formula (VII) is a compound offormula:

In one embodiment, the compound of formula (VII) is:

Compound Structure and Name 13

In one embodiment, the compound of formula (VIII) is a compound offormula:

In one embodiment, the compound of formula (VIII) is a compound offormula:

In one embodiment, the compound of formula (VIII) is:

Compound Structure and Name 4

In one embodiment, the compound of formula (IX) is a compound offormula:

In one embodiment, the compound of formula (IX) is a compound offormula:

In one embodiment, the compound of formula (IX) is:

Compound Structure and Name 5

The present invention also includes the salts and solvate forms of thecompounds described above.

Preferred Substituents

The embodiments described below apply to each compound described hereinwhere appropriate, unless stated otherwise.

-R¹ and -R³

In one embodiment, -R¹ is independently —H or -R^(A).

In one embodiment, -R¹ is independently —H.

In one embodiment, -R¹ is independently -R^(A).

In one embodiment, -R³ is independently —H or -R^(A).

In one embodiment, -R³ is independently —H.

In one embodiment, -R³ is independently -R^(A).

In one embodiment, -R¹ and -R³ are the same.

X

In one embodiment, X is independently selected from CH₂, CHR^(A), CR^(A)₂, NH, NR^(A), O, S, S(O), and S(O)₂

In one embodiment, X is independently selected from CH₂, CHR^(A), CR^(A)₂, NH, and NR^(A).

In one embodiment, X is independently selected from CH₂, CHR^(A), andCR^(A) ₂.

In one embodiment, X is independently CH₂ or CHR^(A).

In one embodiment, X is independently CH₂.

In one embodiment, X is independently CHR^(A).

In one embodiment, X is independently O, S, S(O) or S(O)₂.

In one embodiment, X is independently O or S.

In one embodiment, X is independently NH or NR^(A).

In one embodiment, X is independently NH.

In one embodiment, X is independently NR^(A).

In one embodiment, -L¹- is independently linear saturated C₁₋₆alkylene.

In one embodiment, -L¹- is independently linear saturated C₁₋₅alkylene.

In one embodiment, -L¹- is independently linear saturated C₁₋₃alkylene.

In one embodiment, is independently —CH₂—.

In one embodiment, is independently —CH₂CH₂—.

-T¹

In one embodiment, -T¹ is independently linear saturated C₁₋₆alkyl.

In one embodiment, -T¹ is independently linear saturated C₁₋₅alkyl.

In one embodiment, -T¹ is independently linear saturated C₁₋₃alkyl.

In one embodiment, -T¹ is independently —CH₃.

In one embodiment, -T¹ is independently —CH₂CH₃.

-R⁶, -R⁷, -R⁸, and -R⁹

In one embodiment, -R⁶, -R⁷, -R⁸, and -R⁹ are each independently —H or—P^(A).

In one embodiment, -R⁶ is independently —H.

In one embodiment, -R⁶ is independently —P^(A).

In one embodiment, -R⁷ and -R⁹ are each independently —H.

In one embodiment, -R⁷ and -R⁹ are each independently —P^(A).

In one embodiment, -R⁷ and -R⁹ are the same.

In one embodiment, -R⁸ is independently —H.

In one embodiment, -R⁸ is independently —P^(A).

In one embodiment, -R⁶, -R⁷, and -R⁹ are independently —H.

In one embodiment, -R⁶, -R⁷, -R⁸, and -R⁹ are independently —H.

—R¹⁰

In one embodiment, -R¹⁰ is independently —H or —P^(A).

In one embodiment, -R¹⁰ is independently —H.

In one embodiment, -R¹⁰ is independently —P^(A).

In one embodiment, —R¹⁰ is the same as -R⁶.

—P

In one embodiment, —P is independently optionally substituted pyridineor phenyl.

In one embodiment, —P is independently optionally substituted pyridine.

In one embodiment, —P is independently optionally substituted phenyl.

In one embodiment, —P is optionally substituted with one, two, three orfour groups —P^(A).

In one embodiment, —P is phenyl optionally substituted with one, two,three, four or five groups —P^(A).

In one embodiment, —P is optionally substituted with one group —P^(A).

In one embodiment, —P is independently:

where each of the carbon ring atoms is optionally substituted with agroup —P^(A), and the asterisk indicates the point of attachment.

In one embodiment, —P is independently:

where one of the carbon ring atoms is substituted with a group —P^(A),and the asterisk indicates the point of attachment.

In one embodiment, —P is independently:

where the asterisk indicates the point of attachment.

In one embodiment, —P is unsubstituted.

—P^(A)

In one embodiment, each —P^(A), where present, is independently selectedfrom:

-R^(B),

—OR^(B), -L^(L)-OR^(B),

—F, —Cl, —Br, —I,

—CF₃, —OCF₃,

—NO₂,

—NR^(B) ₂, —NR^(BB)R^(Bc),

-L^(L)-NR^(B) ₂, -L^(L)-NR^(BB)R^(Bc).

In one embodiment, each —P^(A), where present, is independently selectedfrom:

-R⁸,

—OR^(B), -L^(L)-OR^(B),

—F, —Cl, —Br, —I,

—CF₃, —OCF₃,

—NO₂.

In one embodiment, each —P^(A), where present, is independently selectedfrom:

-R⁸,

—OR^(B),

—F, —Cl, —Br, —I,

—CF₃.

In one embodiment, each —P^(A), where present, is independently -R⁸.

In one embodiment, each —P^(A), where present, is independently —F, —Cl,—Br, or —I.

In one embodiment, each —P^(A), where present, is independently —OR^(B).

In one embodiment, each —P^(A), where present, is independently —CF₃.

In one embodiment, each —P^(A), where present, is independently selectedfrom:

—NR⁸ ₂, —NR^(8B)R^(BC),

-L^(L)-NR^(B) ₂, -L^(L)-NR^(BB)R^(BC).

-L^(L)-

In one embodiment, -L^(L)- is independently saturated C₁₋₅alkylene.

In one embodiment, -L^(L)- is independently saturated C₁₋₃alkylene.

In one embodiment, -L^(L)- is independently —CH₂—.

In one embodiment, -L^(L)- is independently —CH₂CH₂—.

-R^(A)

In one embodiment, each -R^(A1), where present, is independently:

—R^(A1), -R^(A2), -R^(A3), -R^(A4), -R^(A5),

-L^(A)-R^(A2), -L^(A)-R^(A3),

-L^(A)-R^(A4), or -L^(A)-R^(A5).

In one embodiment, each -R^(A1), where present, is independently:

-R^(A1), -R^(A4), -R^(A5),

-L^(A)-R^(A4), or -L^(A)-R^(A5).

In one embodiment each -R^(A1), where present, is independently -R^(A1),-R^(A4), or -L^(A)-R^(A4).

In one embodiment, each -R^(A1), where present, is independently—R^(A1).

-R⁸

In one embodiment, each -R^(B1), where present, is independently:

-R^(B1), -R^(B2), -R^(B3), -R^(B4), -R^(B5),

-L^(B)-R^(B2), -L^(B)-R^(B3),

-L^(B)-R^(B4), or -L^(B)-R^(B5).

In one embodiment, each -R^(B1), where present, is independently:

-R^(B1), -R^(B4), -R^(B5),

-L^(B)-R^(B4), or -L^(B)-R^(B5).

In one embodiment, each -R^(B1), where present, is independently-R^(B1), -R^(B4), or -L^(B)-R^(B4).

In one embodiment, each -R^(B1), where present, is independently-R^(B1).

-R^(BB) and -R^(BC)

In one embodiment, -R^(BB) and -R^(BC) taken together with the nitrogenatom to which they are attached, form a 4-, 5-, 6-, or 7-memberednon-aromatic ring having exactly 1 ring heteroatom or exactly 2 ringheteroatoms, wherein one of said exactly 2 ring heteroatoms is N, andthe other of said exactly 2 ring heteroatoms is independently N or O.

In one embodiment, -R^(BB) and -R^(BC) taken together with the nitrogenatom to which they are attached, form a pyrrolidine, piperazine,piperidine, morpholine, or thiomorpholine ring.

In one embodiment, -R^(BB) and -R^(BC) taken together with the nitrogenatom to which they are attached, form a morpholine or thiomorpholinering.

In one embodiment, -R^(BB) and -R^(BS) taken together with the nitrogenatom to which they are attached, form a morpholine ring.

-R^(A1) and -R^(B1)

In one embodiment, each -R^(A1) or each -R^(B1), where present, isindependently saturated aliphatic C₁₋₆alkyl.

In one embodiment, each -R^(A1) or each —R^(B1), where present, isindependently saturated aliphatic C₁₋₆alkyl.

In one embodiment, each -R^(A1) or each —R^(B1), where present, isindependently -Me.

In one embodiment, each -R^(A1) or each —R^(B1), where present, isindependently -Et.

—R^(A2) and -R^(B2)

In one embodiment, each -R^(A2) or each -R^(B2), where present, isindependently saturated C₃₋₈cycloalkyl.

In one embodiment, each -R^(A2) or each -R^(B2), where present, isindependently cyclopropyl.

In one embodiment, each -R^(A2) or each -R^(B2), where present, isindependently cyclohexyl.

-R^(A3) and -R^(B3)

In one embodiment, each -R^(A3) or each -R^(B3), where present, isindependently non-aromatic C₃₋₈heterocyclyl.

In one embodiment, each -R^(A3) or each -R^(B3), if present, is aC₃₋₈heterocyclyl group that is a 4-, 5-, 6-, or 7-membered non-aromaticmonocyclic ring or a 7- or 8-membered non-aromatic bicyclic ring, saidring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms,wherein each of said ring heteroatoms is independently N, O, or S; andis optionally substituted.

In one embodiment, each -R^(A3) or each -R⁸³, if present, isindependently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,tetrahydrofuranyl, or tetrahydropyranyl.

-R^(A4) and -R^(B4)

In one embodiment, each -R^(A4) or each -R^(B4), where present, isindependently C₆₋₁₀carboaryl.

In one embodiment, each -R^(A4) or each -R^(B4), where present, isindependently phenyl.

-R^(A5) and -R^(B5)

In one embodiment, each -R^(A5) or each -R^(B5), if present, isindependently C₅₋₈heteroaryl.

In one embodiment, each -R^(A5) or each -R^(B5), if present, isindependently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, or pyridazinyl, and is optionally substituted.

In one embodiment, each -R^(A5) or each -R^(B5), if present isindependently pyridyl.

-L^(A)- and -L^(B)-

In one embodiment, each -L^(A)- or each -L^(B)-, where present, isindependently saturated C₁₋₃alkylene.

In one embodiment, each -L^(A)- or each -L^(B)-, where present, isindependently —CH₂—.

In one embodiment, each -L^(A)- or each -L^(B)-, where present, isindependently —CH₂CH₂—.

-R^(A1), R^(A2), -R^(A3), -R^(A4), -R^(A5), and -L^(A)

In one embodiment, each -R^(A1), -R^(A2), -R^(A3), -R^(A4), -R^(A5), and-L^(A)-, where present, is optionally substituted, for example, with oneor more substituents.

In one embodiment, each -R^(A1), -R^(A2), -R^(A3), -R^(A4), -R^(A5) and-L^(A)-, where present, is unsubstituted.

In one embodiment, each -R^(A1), -R^(A2), -R^(A3), -R^(A4), -R^(A5), and-L^(A)-, where present, is optionally substituted, for example, with oneor more substituents -R^(AA).

-R^(AA)

In one embodiment, each -R^(AA), where present, is independently:

—F, —Cl, —Br, —I,

-R^(C1),

—CF₃, —OCF₃,

—OH, -L^(C)-OH,

—OR^(C1), -L^(C)-OR^(C1),

—SH, —SR^(C1),

—CN,

—NO₂,

—NH₂, —NHR^(C1), —NR^(C1) ₂, —NR^(C2)R^(C3),

-L^(C)-NH₂, -L^(C)-NHR^(C1), -L^(C)-NR^(C1) ₂, -L^(C)-NR^(C2)R^(C3),

—C(═O)OH, —C(═O)OR^(C1),

—C(═O)NH₂, —C(═O)NHR^(C1), —C(═O)NR^(C1) ₂, or —C(═O)NR^(C2)R^(C3);

wherein:

-   -   each -R^(C1) is independently saturated aliphatic C₁₋₄alkyl,        phenyl, or benzyl;

each -L^(C)- is independently saturated aliphatic C₁₋₅alkylene; and

-   -   in each group —NR^(C2)R^(C3), -R^(C2) and -R^(C3), taken        together with the nitrogen atom to which they are attached, form        a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1        ring heteroatom or exactly 2 ring heteroatoms, wherein one of        said exactly 2 ring heteroatoms is N, and the other of said        exactly 2 ring heteroatoms is independently N or O.

In one embodiment, each -R^(AA), where present, is independently:

—F, —Cl, —Br, —I,

-R^(C1),

—CF₃,

—OH,

—SH, —SR^(C1),

—CN,

—NO₂,

—NH₂, —NR^(C1) ₂, —NR^(C2)R^(C3),

-L^(C)-NH₂, -L^(C)-NHR^(C1), -L^(C)-NR^(C1) ₂, -L^(C)-NR^(C2)R^(C3),

—C(═O)OH, —C(═O)OR^(C1),

—C(═O)NH₂, —C(═O)NHR^(C1), —C(═O)NR^(C1) ₂, or —C(═O)NR^(C2)R^(C3).

In one embodiment, each -R^(AA), where present, is independently:

—F, —Cl, —Br, —I,

-R^(C1),

—CF₃,

—OR^(C1),

—CN,

—NO₂,

—NH₂, —NHR^(C1), —NR^(C1) ₂, —NR^(C2)R^(C3),

-L^(C)-NH₂, -L^(C)-NHR^(C1), -L^(C)-NR^(C1) ₂, -L^(C)-NR^(C2)R^(C3),

—C(═O)OH, —C(═O)OR^(C1),

—C(═O)NH₂, —C(═O)NHR^(C1), —C(═O)NR^(C1) ₂, or —C(═O)NR^(C2)R^(C3).

In one embodiment, each -R^(AA), where present, is independently:

—F, —Cl, —Br, —I,

-R^(C1),

—CF₃,

—OR^(C1),

—NR^(C1) ₂, —NR^(C2)R^(C3),

-L^(C)-NR^(C1) ₂, -L^(C)-NR^(C2)R^(C3),

—C(═O)OH, —C(═O)OR^(C1),

—C(═O)NH₂, —C(═O)NHR^(C1), —C(═O)NR^(C1) ₂, or —C(═O)NR^(C2)R^(C3).

In one embodiment, each -R^(AA), where present, is independently:

—F, —Cl, —Br, —I,

-R^(C1),

—CF₃,

—OR^(C1).

-R^(C1)

In one embodiment, each -R^(C1), where present, is independentlysaturated aliphatic C₁₋₄alkyl, phenyl, or benzyl.

In one embodiment, each -R^(C1), where present, is independentlysaturated aliphatic C₁₋₄alkyl.

In one embodiment, each -R^(C1), where present, is independently phenyl.

In one embodiment, each -R^(C1), where present, is independently benzyl.

-L^(C)-

In one embodiment, each -L^(C)-, where present, is independentlysaturated aliphatic C₁₋₅alkylene.

In one embodiment, each -L^(C)-, where present, is independently —CH₂—.

In one embodiment, each -L^(C)-, where present, is independently—CH₂CH₂—.

-R^(C2) and -R^(C3)

In one embodiment, -R^(C2) and -R^(C3) taken together with the nitrogenatom to which they are attached, form a 4-, 5-, 6-, or 7-memberednon-aromatic ring having exactly 1 ring heteroatom or exactly 2 ringheteroatoms, wherein one of said exactly 2 ring heteroatoms is N, andthe other of said exactly 2 ring heteroatoms is independently N or O.

In one embodiment, -R^(C2) and -R^(C3) taken together with the nitrogenatom to which they are attached, form a pyrrolidine, piperazine,piperidine, morpholine, or thiomorpholine ring.

In one embodiment, —R^(C2) and -R^(C3) taken together with the nitrogenatom to which they are attached, form a morpholine or thiomorpholinering.

In one embodiment, -R^(C2) and -R^(C3) taken together with the nitrogenatom to which they are attached, form a morpholine ring.

Y

In one embodiment, Y is independently S or O.

In one embodiment, Y is independently S

In one embodiment, Y is independently O.

In one embodiment, Y is S where one of -R^(N1) and -R^(N2) is other than—H.

In one embodiment, Y is O where -R^(N1) and -R^(N2) are each —H.

-R^(N1) and -R^(N2)

In one embodiment, -R^(N1) and -R² are each independently selected from—H or saturated C₁₋₆alkyl.

In one embodiment, -R^(N1) is independently —H.

In one embodiment, -R^(N1) is independently saturated C₁₋₆alkyl.

In one embodiment, -R^(N1) is independently saturated aliphaticC₁₋₆alkyl.

In one embodiment, -R^(N1) is independently -Et.

In one embodiment, -R^(N2) is independently —H.

In one embodiment, -R^(N2) is independently saturated C₁₋₅alkyl.

In one embodiment, -R^(N2) is independently saturated aliphaticC₁₋₆alkyl.

In one embodiment, -R^(N2) is independently -Et.

In one embodiment, -R^(N1) and -R^(N2) are the same.

In one embodiment, -R^(N1) and -R^(N2) are different.

In one embodiment, -R^(N1) and -R^(N2) are each —H.

In one embodiment, -R^(N1) and -R^(N2) are each -Et.

In one embodiment, -R^(N1) and -R^(N2) taken together with the nitrogenatom to which they are attached, form a 5-, 6-, or 7-memberednon-aromatic ring having exactly 1 ring heteroatom or exactly 2 ringheteroatoms, wherein one of said exactly 2 ring heteroatoms is N, andthe other of said exactly 2 ring heteroatoms is independently N, O, orS.

In one embodiment, -R^(N1) and -R^(N2) taken together with the nitrogenatom to which they are attached, form a 6-membered non-aromatic ringhaving exactly 1 ring heteroatom or exactly 2 ring heteroatoms, whereinone of said exactly 2 ring heteroatoms is N, and the other of saidexactly 2 ring heteroatoms is independently N, O, or S.

In one embodiment, -R^(N1) and —R^(N2) taken together with the nitrogenatom to which they are attached, form a pyrrolidine, piperazine,piperidine, morpholine, or thiomorpholine ring.

In one embodiment, -R^(N1) and -R^(N2) taken together with the nitrogenatom to which they are attached, form a morpholine or thiomorpholinering.

In one embodiment, -R^(N1) and -R^(N2) taken together with the nitrogenatom to which they are attached, form a morpholine ring.

4a and 9a Bond

In one embodiment, the dashed line indicates that the bond is a singlebond or a double bond between the 4a and 9a atoms.

In one embodiment, the dashed line indicates that the bond is a singlebond between the 4a and 9a atoms.

In one embodiment, the dashed line indicates that the bond is a doublebond between the 4a and 9a atoms.

Combinations

Each and every compatible combination of the embodiments describedabove, and below, is explicitly disclosed herein, as if each and everycombination was individually and explicitly recited.

Substantially Purified Forms

One aspect of the present invention pertains to compounds, as describedherein, in substantially purified form and/or in a form substantiallyfree from contaminants.

In one embodiment, the substantially purified form is at least 50% byweight, e.g., at least 60% by weight, e.g., at least 70% by weight,e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., atleast 95% by weight, e.g., at least 97% by weight, e.g., at least 98% byweight, e.g., at least 99% by weight.

In one embodiment, the contaminants represent no more than 50% byweight, e.g., no more than 40% by weight, e.g., no more than 30% byweight, e.g., no more than 20% by weight, e.g., no more than 10% byweight, e.g., no more than 5% by weight, e.g., no more than 3% byweight, e.g., no more than 2% by weight, e.g., no more than 1% byweight.

Salts

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the compound. For example, if the compound isanionic, or has a functional group which may be anionic (e.g., —COOH maybe —COO⁻), then a salt may be formed with a suitable cation. Examples ofsuitable inorganic cations include, but are not limited to, alkali metalions such as Na⁺ and K⁺, alkaline earth cations such as Ca²⁺ and Mg²⁺,and other cations such as Al⁺³. Examples of suitable organic cationsinclude, but are not limited to, ammonium ion (i.e., NH₄ ⁺) andsubstituted ammonium ions (e.g., NH₃R⁺, NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺).Examples of some suitable substituted ammonium ions are those derivedfrom: ethylamine, diethylamine, dicyclohexylamine, triethylamine,butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, aswell as amino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, trifluoroacetic, andvaleric. Examples of suitable polymeric organic anions include, but arenot limited to, those derived from the following polymeric acids: tannicacid, carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound alsoincludes salt forms thereof.

Solvates and Hydrates

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the compound. The term “solvate” is used hereinin the conventional sense to refer to a complex of solute (e.g.,compound, salt of compound) and solvent. If the solvent is water, thesolvate may be conveniently referred to as a hydrate, for example, amono-hydrate, a di-hydrate, a tri-hydrate, etc.

Unless otherwise specified, a reference to a particular compound alsoincludes solvate and hydrate forms thereof.

Formulations

The compounds of formula (I) may be provided in a composition orformulation for administration to a subject, for example a subjecthaving AD. While it is possible for the compound to be used (e.g.,administered) alone, it is often preferable to present it as acomposition or formulation.

In one aspect of the invention there is provided a method of preparing acomposition or formulation comprising a compound of formula (I). Themethod includes the synthesis of a compound of formula (I) comprisingone or more of the steps described herein. In one embodiment, the methodfurther comprises the step of admixing at least one compound of formula(I), as defined herein, together with one or more other pharmaceuticallyacceptable ingredients well known to those skilled in the art, e.g.,carriers, diluents, excipients, etc. If formulated as discrete units(e.g., tablets, etc.), each unit contains a predetermined amount(dosage) of the active compound.

In one embodiment, the composition is a pharmaceutical composition(e.g., formulation, preparation, medicament) comprising a compound offormula (I), as described herein, and a pharmaceutically acceptablecarrier, diluent, or excipient.

In one embodiment, the composition is a pharmaceutical compositioncomprising at least one compound of formula (I), as described herein,together with one or more other pharmaceutically acceptable ingredientswell known to those skilled in the art, including, but not limited to,pharmaceutically acceptable carriers, diluents, excipients, adjuvants,fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers,solubilisers, surfactants (e.g., wetting agents), masking agents,colouring agents, flavouring agents, and sweetening agents.

In one embodiment, the composition further comprises other activeagents, for example, other therapeutic or prophylactic agents.

Suitable carriers, diluents, excipients, etc. can be found in standardpharmaceutical texts. See, for example, Handbook of PharmaceuticalAdditives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (SynapseInformation Resources, Inc., Endicott, New York, USA); Remington: TheScience and Practice of Pharmacy, 20th Edition (ed. Gennaro et al.),2000, Lippincott, Williams & Wilkins, Baltimore; and Handbook ofPharmaceutical Excipients, 2nd Edition (eds A. Wade and P. J. Weller),1994, American Pharmaceutical Association, Washington and ThePharmaceutical Press, London.

The term “pharmaceutically acceptable,” as used herein, pertains tocompounds, ingredients, materials, compositions, dosage forms, etc.,which are, within the scope of sound medical judgment, suitable for usein contact with the tissues of the subject in question (e.g., human)without excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio. Each carrier, diluent, excipient, etc. must also be “acceptable”in the sense of being compatible with the other ingredients of theformulation.

The formulations may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association theactive compound with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the active compound with carriers(e.g., liquid carriers, finely divided solid carrier, etc.), and thenshaping the product, if necessary.

The formulation may be prepared to provide for rapid or slow release;immediate, delayed, timed, or sustained release; or a combinationthereof.

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the activeingredient is dissolved, suspended, or otherwise provided (e.g., in aliposome or other microparticulate). Such liquids may additional containother pharmaceutically acceptable ingredients, such as anti-oxidants,buffers, preservatives, stabilisers, bacteriostats, suspending agents,thickening agents, and solutes which render the formulation isotonicwith the blood (or other relevant bodily fluid) of the intendedrecipient. Examples of excipients include, for example, water, alcohols,polyols, glycerol, vegetable oils, and the like. Examples of suitableisotonic carriers for use in such formulations include Sodium ChlorideInjection, Ringer's Solution, or Lactated Ringer's Injection. Typically,the concentration of the active ingredient in the liquid is from about 1ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1μg/ml. The formulations may be presented in unit-dose or multi-dosesealed containers, for example, ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules, and tablets.

Use of Compounds and Compositions in Therapy

In one aspect the present invention provides compounds of formula (I)and formulations comprising compounds of formula (I) as described hereinfor use in therapy.

In other aspects, the invention pertains to compounds obtained orobtainable by the methods described herein for use in therapy.

Doody at el. have noted that Dimebon weakly inhibitsbutyrylcholinesterase and acetyl cholinesterase, weakly blocks theN-methyl-D-aspartate receptor signalling pathway, and inhibitsmitochondrial permeability transition pore opening.

Yamashita et al. have noted that Dimebon inhibits aggregation of TDP-43in cellular models of amyotrophic lateral sclerosis (ALS) andfrontotemporal lobar degeneration with ubiquinated inclusions (FLTD-U).

Dimebon has also shown neuroprotective effects in models for Alzheimer'sdisease and Huntington's disease.

The compounds and compositions described herein may reverse or inhibitthe aggregation of tau protein (e.g. in the form of paired helicalfilaments (PHFs), optionally in neurofibrillary tangles (NFTs)) in thebrain of a mammal.

As discussed below, various tauopathy disorders that have beenrecognized which feature prominent tau pathology in neurons and/or gliaand this term has been used in the art for several years. Thesimilarities between these pathological inclusions and thecharacteristic tau inclusions in diseases such as AD indicate that thestructural features are shared and that it is the topographicdistribution of the pathology that is responsible for the differentclinical phenotypes observed. In addition to specific diseases discussedbelow, those skilled in the art can identify tauopathies by combinationsof cognitive or behavioural symptoms, plus additionally through the useof appropriate ligands for aggregated tau as visualised using PET orMRI, such as those described in WO02/075318.

One aspect of the present invention pertains to a method of treatment orprophylaxis of a tauopathy condition in a patient, comprisingadministering to said patient a therapeutically-effective amount of acompound of formula (I), as described herein.

Aspects of the present invention relate to “tauopathies”. As well asAlzheimer's disease (AD), the pathogenesis of neurodegenerativedisorders such as Pick's disease and Progressive Supranuclear Palsy(PSP) appears to correlate with an accumulation of pathologicaltruncated tau aggregates in the dentate gyrus and stellate pyramidalcells of the neocortex, respectively. Other dementias includefronto-temporal dementia (FTD); FTD with parkinsonism linked tochromosome 17 (FTDP-17); disinhibition-dementia-parkinsonism-amyotrophycomplex (DDPAC); pallido-ponto-nigral degeneration (PPND);Guam-amyotrophic lateral sclerosit (ALS) syndrome; pallido-nigro-luysiandegeneration (PNLD); cortico-basal degeneration (CBD); Dementia withArgyrophilic grains (AgD); Dementia pugilistica (DP) wherein despitedifferent topography, NFTs are similar to those observed in AD (H of P.R., Bouras C., Buee L., Delacourte A., Peri D. P. and Morrison J. H.(1992) Differential distribution of neurofibrillary tangles in thecerebral cortex of dementia pugilistica and Alzheimer's disease cases.Acta Neuropathol. 85, 23-30). Chronic traumatic encephalopathy (CTE), atauopathy including DP as well as repeated and sports-related concussion(McKee, A., Cantu, R., Nowinski, C., Hedley-Whyte, E., Gavett, B.,Budson, A., Santini, V., Lee, H.-S., Kubilus, C. & Stern, R. (2009)Chronic traumatic encephalopathy in athletes: progressive tauopathyafter repetitive head injury. Journal of Neuropathology & ExperimentalNeurology 68, 709-735). Others are discussed in Wischik et al. 2000,loc. cit, for detailed discussion—especially Table 5.1).

Abnormal tau in NFTs is found also in Down's Syndrome (DS) (Flament S.,Delacourte A. and Mann D. M. A. (1990) Phosphorylation of tau proteins:a major event during the process of neurofibrillary degeneration. Acomparative study between AD and Down's syndrome. Brain Res., 516,15-19). Also Dementia with Lewy bodies (DLB) (Harrington, C. R., Perry,R. H., Perry, E. K., Hurt, J., McKeith, I. G., Roth, M. & Wischik, C. M.(1994) Senile dementia of Lewy body type and Alzheimer type arebiochemically distinct in terms of paired helical filaments andhyperphosphorylated tau protein. Dementia 5, 215-228). Tau-positive NFTsare also found in Postencephalitic parkinsonism (PEP) (Hof P. R.,Charpiot, A., Delacourte A., Buee, L., Purohit, D., Perl D. P. andBouras, C. (1992) Distribution of neurofibrillary tangles and senileplaques in the cerebral cortex in postencephalitic parkinsonism.Neurosci. Lett. 139, 10-14). Glial tau tangles are observed in Subacutesclerosing panencephalitis (SSPE) (Ikeda K., Akiyama H., Kondo H., AraiT., Arai N. and Yagishita S. (1995) Numerous glial fibrillary tangles inoligodendroglia in cases of subacute sclerosing panencephalitis withneurofibrillary tangles. Neurosci. Lett., 194, 133-135).

Additionally there is a growing consensus in the literature that a taupathology may also contribute more generally to cognitive deficits anddecline, including in mild cognitive impairment (MCI) (see e.g. Braak,H., Del Tredici, K, Braak, E. (2003) Spectrum of pathology. In Mildcognitive impairment: Aging to Alzheimer's disease edited by Petersen,R. C.; pp. 149-189).

In this and all other aspects of the invention relating to tauopathies,preferably the tauopathy is selected from the list consisting of theindications above, i.e., AD, Pick's disease, PSP, FTD, FTDP-17, DDPAC,PPND, Guam-ALS syndrome, PNLD, and CBD and AgD, DS, SSPE, DP, PEP, DLB,CTE and MC1.

In one preferred embodiment the tauopathy is Alzheimer's disease (AD).

One aspect of the present invention pertains to a compound of formula(I), as described herein, for use in a method of treatment orprophylaxis (e.g., of a tauopathy condition) of the human or animal bodyby therapy.

One aspect of the present invention pertains to use of a compound offormula (I), as described herein, in the manufacture of a medicament foruse in the treatment or prophylaxis of a tauopathy condition.

A further embodiment is a method of treatment or prophylaxis of adisease of tau protein aggregation as described herein, which methodcomprises administering to a subject a compound of formula (I), ortherapeutic composition comprising the same, such as to inhibit theaggregation of the tau protein associated with said disease state.

EXAMPLES

The following syntheses are provided solely for illustrative purposesand are not intended to limit the scope of the invention, as describedherein.

Synthesis 1a 6-Methyl-3-pyridylthioacetmorpholide

5-Acetyl-2-methylpyridine (36.75 mmol, 5.00 g), morpholine (1.7 eq.,62.475 mmol, 5.44 g, 5.46 cm³), and sulphur (1.6 eq., 58.8 mmol, 1.88 g)were combined in a flask and heated at reflux for 17 hours. The reactionwas then cooled to room temperature, and poured into water (100 cm³).The resulting opaque solution was extracted with CHCl₃ (3×100 cm³). Thecombined extracts were dried (MgSO₄), and the solvent removed to yield adark oil. Light petrol (50 cm³) was added to this oil, stirredvigorously, and the resulting mixture evaporated to yield a crude yellowsolid, which was filtered, and washed with additional petrol (50 cm³) togive the product (9.338 g, 93.3%).

δ_(H) (250 MHz, CDCl₃) 8.31 (1H, s, Ar), 7.58 (1H, d, J 7.7, Ar), 7.06(1H, d, J 7.7, Ar), 4.26 (2H, t, J 4.3, CH₂), 4.20 (2H, s, CH₂), 3.60(2H, t, J 4.3, CH₂), 2.47 (3H, s, CH₃); δ_(C) (62.5 MHz, CDCl₃) 199.1(C═S), 157.4 (Ar), 148.5 (Ar), 135.8 (Ar), 128.4 (Ar), 123.4 (Ar), 66.3(CH₂), 50.6 (CH₂), 50.1 (CH₂), 24.0 (CH₃).

The synthesis of this compound has been described previously by Sperberet al.

Synthesis 1b i) 5-Acetyl-2-methylpyridine (method of Masamichi Maruokaet al.)

The reactor was charged with 5-ethyl-2-methylpyridine (200 cm³, 1.5 mol)and cooled to 5° C. Concentrated H₂SO₄ (132 cm³, 1.3 mol) was addedcautiously, and the medium stirred for 15 minutes until homogeneous andadequately cool. AcOH (236 cm³, 4.1 mol) was added, followed by Ac₂O(173 cm³, 2.4 mol) and the medium stirred for 15 minutes. Solid CrO₃(212 g, 2.12 mol) was added cautiously over ˜3 hours taking great careto keep the internal temperature between 10-20° C. The reaction was thenallowed to stir at 20° C. for an additional 3 hours. The crude reactionmedium was poured onto ice (1 kg), and this aqueous medium returned tothe reactor vessel, and cautiously made basic with solid Na₂CO₃. CHCl₃(1 L) was added, and the reactor stirred vigorously for 10 mins. Theorganic phase was collected. This extraction process was repeated afurther 2 times. The combined organics are dried (MgSO₄) and solventremoved.

The resulting brown oil was a mixture of starting material and product(typically 2:1). Starting material can be recovered by vacuumdistillation (bp. 35-42° C. @ 10 mmHg) to leave a brown residue (63.6 g,31%) which gives a ¹H NMR spectrum consistent with5-acetyl-2-methylpyridine.

δ_(H) (250 MHz, CDCl₃) 8.82 (1H, s, Ar), 7.91 (1H, d, J 7.7, Ar), 7.06(1H, d, J 7.7, Ar), 2.40 (6H, s, CH₃);

ii) 6-Methyl-3-pyridylthioacetmorpholide hydrochloride

5-Acetyl-2-methylpyridine (63 g, 471 mmol), morpholine (70 cm³, 800mmol), and sulphur (24 g, 753 mmol) were combined in a flask and heatedto reflux for 16 hours.

The reaction was then cooled to room temperature, and poured into H₂O (1L). This opaque solution was extracted with CHCl₃ (3×1 L). The combinedextracts were dried (MgSO₄), and solvent removed to yield a dark oil.This was diluted to 500 cm³ with THF, and concentrated HCl added (30cm³). The precipitated product was isolated by filtration to yield thehydrochloride salt as a light brown solid (113 g, 87.9%).

δ_(H) (250 MHz, CDCl₃) 8.58 (1H, s, Ar), 8.37 (1H, d, J 8.0, Ar), 7.85(1H, d, J 8.0, Ar), 4.35 (2H, s, CH₂), 4.20 (2H, mult, CH₂), 3.90 (2H,mult, CH₂), 3.77 (4H, m, CH₂), 2.74 (3H, s, CH₃).

Synthesis 2 N,N-Diethyl-2-(6-methyl-pyridin-3-yl)-thioacetamide

The procedure was the same as that used in example 1 above. Thus,5-acetyl-2-methylpyridine (7.4 mmol, 1.00 g), diethylamine (1.7 eq.,12.5 mmol, 0.919 g, 1.3 cm³), and sulphur (1.6 eq., 11.84 mmol, 0.379 g)were refluxed and worked up as previously described. Treatment of thecrude residue with petrol did not induce crystallisation, so the titlecompound was isolated by flash chromatography, first eluting impuritieswith 1:1 petrol/EtOAc, then eluting the product with EtOAc (R_(f)=0.392in EtOAc). The product was obtained as a yellow oil (0.606 g, 36.8%).

δ_(H) (250 MHz, CDCl₃) 8.14 (1H, s, Ar), 7.38 (1H, d, J 7.9, Ar), 6.90(1H, d, J 7.9, Ar), 3.96 (2H, s, CH₂), 3.74 (2H, q, J 7.0 CH₂), 3.28(2H, q, J 7.0, CH₂), 2.28 (3H, s, CH₃), 1.02 (3H, t, J 7.0, CH₃), 0.94(3H, t, J 7.0, CH₃); 6c (62.5 MHz, CDCl₃) 197.8 (C═S), 156.7 (Ar), 148.5(Ar), 135.9 (Ar), 129.1 (Ar), 123.1 (Ar), 47.6 (CH₂), 46.5 (CH₂), 46.4(CH₂), 23.8 (CH₃), 13.4 (CH₃), 11.0 (CH₃).

Synthesis 3 2-(6-Methyl-pyridin-3-yl)-acetamide

To a Schlenk tube charged with 5-acetyl-2-methylpyridine (937 mg, 6.9mmol, 1.0 eq), was added ammonia solution (35% wt/vol, 1.20 cm³, 25mmol, 3.6 eq) and pyridine (1 cm³). The vessel was sealed and thehomogeneous solution shaken vigorously, and allowed to stand for 30minutes. Sulfur (1.25 g, 38.9 mmol, 5.6 eq) was then added, and thevessel sealed, and heated to 160° C. for 17 hours. The cooled reactionmedium was rinsed into a round bottom flask using the minimum quantityof distilled water (˜5 cm³), and solvent removed in vacuo to leave asolid yellow residue, which was purified by column chromatography,eluting with 4:1 EtOAc/MeOH and collecting the fraction withR_(f)=0.282, to yield the desired product as fine colourless needles(151 mg, 15%).

mp 175-177° C. (lit 168-169° C.); δ_(H) (250 MHz; CD₃OD) 8.27 (1H, s,Ar), 7.59 (1H, d, J 8.1, Ar), 7.19 (1H, d, J 8.1, Ar), 4.75 (2H, s,NH₂), 3.46 (2H, s, CH₂), 2.47 (3H, s, CH₃).

The title product may be hydrolysed to the corresponding carboxylic acidby hydrolysis as exemplified below for the thioamide compounds.

Synthesis 4a 6-Methyl-3-pyridineacetic acid

Crude 2-(6-methyl-pyridin-3-yl)-1-morpholin-4-yl-ethanethione (39.5mmol, 9.685 g) was suspended in 2:1 H₂O/EtOH (40 mL). NaOH (3.3 eq.,118.5 mmol, 4.8 g) was added and the reaction heated to reflux for 16hours. The volatiles were then removed from the cooled reaction medium,and the pH adjusted to precisely pH 7.0 with 3.0 M HCl. The solvent wasremoved and the residue slurried in boiling methanol, filtered whilsthot, and the filtrate evaporated to dryness. This crude product containsresidual free morpholine, which was removed by flash columnchromatography, eluting with 9:1 EtOAc/MeOH. The fractions were analysedby TLC eluting with 1:1 EtOAc/MeOH (R_(f)=0.209). The product wasobtained in 46% yield.

δ_(H) (250 MHz, CD₃OD) 8.33 (1H, s, Ar), 7.69 (1H, d, J 7.9, Ar), 7.28(1H, d, J 7.9, Ar), 3.59 (2H, s, CH₂), 2.51 (3H, s, CH₃); δ_(C) (62.5MHz, CD₃OD) 176.6 (C═O), 157.1 (Ar), 150.0 (Ar), 140.3 (Ar), 131.4 (Ar),125.0 (Ar), 40.3 (CH₂), 23.3 (CH₃).

Synthesis 4b 6-Methyl-3-pyridineacetic acid (modified method)

Crude 2-(6-Methyl-pyridin-3-yl)-1-morpholin-4-yl-ethanethione (39.5mmol, 9.685 g) was suspended in 2:1 H₂O/EtOH (75 cm³). NaOH (3.3 eq.,118.5 mmol, 4.8 g) added and the reaction heated to reflux for 16 hours.Volatiles were then removed from the cooled reaction medium, and theaqueous residue extracted with DCM (3×50 cm³). The pH was adjusted toprecisely pH 7.0 with HCl, and a further DCM extraction performed (3×50cm³). Water was removed from the residue, and the obtained solidsslurried in methanol, filtered, and the filtrate evaporated to dryness.The orange solid obtained gave spectroscopic data consistent with thedesired product. Mass recovery is typically >100% however this is due toNaCl within the product.

The synthesis of this compound has been described previously by Sperberet al.

This compound has been obtained in crystalline form and a single crystalX-ray structure obtained. Crystallographic data sets were collected on aBruker Smart APEX2, at 150K, using a full-matrix least-squaresrefinement on F2.

Synthesis 5 6-Methyl-3-pyridineacetic acid

Crude N,N-diethyl-2-(6-methyl-pyridin-3-yl)-thioacetamide was hydrolysedwith NaOH as described above in Synthesis 4a. The product acid wasobtained in 28% yield after purification.

The analytical data were identical to those reported above in Synthesis4.

Synthesis 6 2-(6-Methyl-pyridin-3-yl)-N-p-tolyl-acetamide

Carbodiimide Method

(6-Methyl-pyridin-3-yl)-acetic acid (500 mg, 3.3 mmol) was added to DCM(50 cm³). Et₃N (1.0 eq., 0.4 cm³) was then added, followed byp-toluidine (1.5 eq., 4.96 mmol, 531 mg) and DCC (1.1 eq., 3.64 mmol,750 mg). The cloudy solution was stirred at room temperature under anargon atmosphere for 6 hours, filtered, and the solvent removed. Thecrude product was purified by flash chromatography, eluting with EtOAc,and collecting the product as the fraction with R_(f)=0.375 (9% yield).

Mixed Anhydride Method (1)

(6-Methyl-pyridin-3-yl)-acetic acid (1.0 g, 6.61 mmol) was placed in adry flask under an argon atmosphere. Dry THF (100 cm³) was added,followed by N-methylmorpholine (1.0 eq., 6.61 mmol, 0.668 g, 0.73 cm³).The solution was cooled to −78° C. iso-Butyl chloroformate (1.2 eq.,7.932 mmol, 1.08 g, 1.0 cm³) was added, and the solution stirred for 30min. p-Toluidine (1.0 eq., 6.61 mmol, 0.707 g) was added, and thereaction allowed to warm to room temperature, then stirred for 16 hours.Volatiles were then removed from the reaction, and the residuepartitioned between 10% aq. NaHCO₃ solution (100 cm³) and DCM (100 cm³).The organic layer was separated and washed with water (100 cm³), dried(MgSO₄), and solvent removed, to yield a pale yellow solid. This solidwas recrystallised from THF (0.494 g, 31%).

The product can be further purified by flash chromatography, elutingwith EtOAc, and collecting the product as the fraction with R_(f)=0.375.

Mixed Anhydride Method (2)

(6-Methyl-pyridin-3-yl)-acetic acid (1.0 g, 6.6 mmol) was placed in aflask under an argon atmosphere, and dry DMF (100 cm³) added, followedby Bu₄NBF₄ (218 mg, 0.66 mmol). The solution was stirred for 5 minutesto favour homogeneity, and then cooled to an internal temperature of˜−40° C. N-methylmorpholine (0.75 cm³, 6.6 mmol) was added, followed byisobutyl chloroformate (0.83 cm³, 13.6 mmol). The solution was stirredat this temperature 30 minutes, p-toluidine (710 mg, 6.6 mmol) added,and the coolant removed. The solution was stirred at room temperatureunder argon for a further 16 hours. Volatiles were then removed byvacuum distillation, and the residue dissolved in CHCl₃ (50 cm³), washedsequentially with 10% NaHCO₃ solution (50 cm³), H₂O (50 cm³), and dried(MgSO₄). Removal of solvent furnished a crude yellow solid which waspurified by flash column chromatography on SiO₂ (10×5 cm) eluting withEtOAc. The desired product was obtained as colourless prisms (1.13 g,71.0%).

δ_(H) (250 MHz, CDCl₃) 8.35 (1H, s, NH), 8.30 (1H, s, Ar), 7.59 (1H, d,J 8.2, Ar), 7.32 (2H, d, J 7.9, Ph), 7.10 (1H, d, J 8.2, Ar), 7.02 (2H,d, J 7.9, Ph), 3.57 (2H, s, CH₂), 2.51 (3H, s, CH₃), 2.26 (3H, s, CH₃);δ_(C) (62.5 MHz, CDCl₃) 168.6 (C═O), 157.4 (Ar), 149.4 (Ar), 137.4 (Ph),135.3 (Ar), 134.2 (Ar), 129.4 (Ph), 127.8 (Ar), 123.5 (Ph), 120.2 (Ph),40.9 (CH₂), 24.0 (CH₃), 20.9 (CH₃). MS (Cl⁺): calc. 241.1341, found241.1340 [M+H]⁺; mp 146-150° C.

This compound has been obtained in crystalline form and a single crystalX-ray structure obtained. Crystallographic data sets were collected on aBruker Smart APEX2, at 150K, using a full-matrix least-squaresrefinement on F2.

Synthesis 7a [2-(6-Methyl-pyridin-3-yl)-ethyl]-p-tolyl-amine

2-(6-Methyl-pyridin-3-yl)-N-p-tolyl-acetamide (0.960 g, 4 mmol) wasdissolved in dry THF (20 cm³), and cooled to 0° C. LiAlH₄ (5.0 eq., 20mmol, 10 ml of a 2.0 M solution in THF) was added dropwise at first,until no more gas evolution was observed (˜0.5 ml), and then theremaining LiAlH₄ solution was added in one portion. The resultingsolution was heated to reflux for 16 hours with stirring. Wet diethylether was then added until no further gas evolution was observed, theresulting medium filtered, and the residue washed with ether (˜50 cm³).The filtrate was dried (MgSO₄), and the solvent removed to yield a crudeyellow oil. The oil was purified by flash chromatography, eluting with1:1 petrol (40-60)/EtOAc. The product was collected as the fraction withR_(f)=0.294. The product was obtained as a pale yellow oil (254 mg,28%).

The conditions for the reaction were modified in order to improve theyield of the amine product. The modified conditions used and the resultsof reactions using those conditions are set out in Table 1 below.

TABLE 1 Concen- Reaction Amide THF tration time Conversion YieldReaction (mmol) (cm³) (M) (h) (%) (%) Unmodified 4.0 20 0.2 16 68 28.0 10.3 3 0.1 20 NA 23.0 2 2.3 20 0.1 40 NA 21.3 3 2.0 5 0.4 16 94 71.1

The molar amount of reducing agent with respect to the amide was heldconstant. Higher yield of product were obtained at higher concentrationsof amide in the reaction medium.

The conversion figure is the percentage of desired product in the crudeproduct mixture to the total amount of starting material and desiredproduct. The percentage was calculated from the ¹H NMR integral valuesfor a singlet proton in the pyridine ring of the product and startingmaterial.

δ_(H) (250 MHz, CDCl₃) 8.34 (1H, s, Ar), 7.39 (2H, d, J 7.9, Ar), 7.07(1H, d, J 7.9, Ar), 6.97 (2H, d, J 7.9, Ph), 6.51 (2H, d, J 7.9, Ph),3.35 (2H, t, J 6.7, CH₂), 2.84 (2H, t, J 6.7, CH₂), 2.52 (3H, s, CH₃),2.22 (3H, s, CH₃). δ_(C) (62.5 MHz, CDCl₃) 159.5 (Ar), 149.3 (Ar), 145.4(Ar), 136.7 (Ph), 131.7 (Ar), 129.9 (Ph), 126.9 (Ar), 123.1 (Ph), 113.2(Ph), 45.2 (CH₂), 32.3 (CH₂), 24.0 (CH₃), 20.4 (CH₃). MS (Cl⁺): calc.227.1548, found 227.1548 [M+H]⁺.

Synthesis 7b [2-(6-Methyl-pyridin-3-yl)-ethyl]-p-tolyl-amine (modifiedmethod)

2-(6-Methyl-pyridin-3-yl)-N-p-tolyl-acetamide (0.25 g, 1 mmol) wasdissolved in DCM (5 cm³) under an argon atmosphere. Bu₄NBH₄ (0.8 g, 3mmol) was added in one portion. The resulting solution was heated toreflux for 16 hours with stirring. Volatiles were then removed in vacuoand the residue suspended in 1.0 M HCl (5 cm³) and heated to reflux for20 minutes. Na₂CO₃ was then added to the cooled solution until nofurther gas evolution was observed. The solution was extracted with Et₂O(3×5 cm³), the extracts combined, washed with H₂O (20 cm³), dried(MgSO₄), and solvent removed to yield a tacky yellow oil (217 mg, 96%).NMR spectroscopy of this oil, showed the desired product was present ingood purity.

δ_(H) (250 MHz, CDCl₃) 8.34 (1H, s, Ar), 7.39 (2H, d, J 7.9, Ar), 7.07(1H, d, J 7.9, Ar), 6.97 (2H, d, J 7.9, Ph), 6.51 (2H, d, J 7.9, Ph),3.35 (2H, t, J 6.7, CH₂), 2.84 (2H, t, J 6.7, CH₂), 2.52 (3H, s, CH₃),2.22 (3H, s, CH₃); δ_(c) (62.5 MHz, CDCl₃) 159.5 (Ar), 149.3 (Ar), 145.4(Ar), 136.7 (Ph), 131.7 (Ar), 129.9 (Ph), 126.9 (Ar), 123.1 (Ph), 113.2(Ph), 45.2 (CH₂), 32.3 (CH₂), 24.0 (CH₃), 20.4 (CH₃);

The inventors have used compound 1, as synthesised by the methodsdescribed herein, to prepare dimebon.

Synthesis 8 2-Methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine

[2-(6-Methyl-pyridin-3-yl)-ethyl]-p-tolyl-amine (693.4 mg, 3 mmol) wasdissolved in EtOH (8 cm³) and HCl added (3 cm³ of a 1.0 M solution, 3mmol). The resulting solution was cooled to 5° C. NaONO (232.5 mg, 3.37mmol) was dissolved in H₂O (2 cm³) and cooled to 5° C., before beingadded slowly to the starting material solution, such that the internaltemperature remained between 5-10° C. The reaction was allowed to attainroom temperature, stoppered, and stirred for an additional 18 hours. Thestopper was then removed and a gentle air stream blown across the mediumto remove EtOH. The resulting crystalline precipitate was removed byfiltration, washed with H₂O (10 cm³) and placed in a desiccator overSiO₂ until required (612 mg, 78%).

Synthesis 9 N-[2-(6-Methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine

Crude 2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine (612 mg, 2.4mmol) was dissolved in dry THF (20 cm³) in a dry 3-neck flask under anargon atmosphere and cooled until the internal temperature was between0-5° C. Solid LiAlH₄ (290 mg, 7.7 mmol) was added and the reactionallowed to warm to room temperature. Following 2 hours stirring at roomtemperature, the reaction was again cooled to 0° C., and quenched withMeOH until no further gas evolution was observed (˜3 cm³). SaturatedNaOH solution was then added (3 cm³), followed by H₂O (3 cm³), and themedium extracted with CHCl₃ (3×50 cm³), the combined extracts were dried(MgSO₄), and solvent removed in vacuo to yield a crude orange oil. Thiscould be carried forward to the next step if desired, or stored below 5°C. until required.

Synthesis 10N′-(1-Methyl-piperidin-4-ylidene)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine

The crude N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine wasdissolved in benzene (20 cm³) and 4 Å molecular sieves added (˜5 g),followed by 1-methylpiperidin-4-one (346 μL, 3.0 mmol). The reaction washeated to reflux for 2 hours, cooled, and filtered. Solvent was removedin vacuo to yield a crude orange oil.

Synthesis 112,8-Dimethyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Dimebon)

Concentrated HCl (6 cm³) was added to EtOH (4 cm³). The crudeN′-(1-methyl-piperidin-4-ylidene)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazinewas dissolved in this ethanolic HCl and heated to 100° C. for 30minutes. The reaction was then cooled, and diluted with H₂O (10 cm³),saturated with Na₂CO₃, and extracted with CHCl₃ (3×50 cm³). The combinedextracts were dried (MgSO₄) and solvent removed. The residual brown oilwas purified by flash column chromatography over SiO₂ (10×2 cm) elutingwith 1:1 EtOAc/MeOH to provide the desired product as a pale brownpowder (612 mg, 63% yield over 3 steps based on last pure startingmaterial (2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine)).

δ_(H) (250 MHz, CDCl₃) 8.23 (1H, s, Ar), 7.20 (1H, s, Ar), 7.13 (1H, d,J 7.8, Ar), 7.05 (1H, d, J 7.6, Ar), 6.97 (2H, d, J 8.2, 2×Ar), 4.17(2H, t, J 7.0, CH₂), 3.65 (2H, s, CH₂), 2.95 (2H, t, J 7.0, CH₂), 2.72(2H, t, J 5.5, CH₂), 2.51 (11H, m); MS (EI⁺): calc. m/z 319.2048, found319.2042 (M⁺).

Synthesis 128-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-1,3,4,5-tetrahydro-thiopyrano[4,3-b]indole

The method was the same as for Dimebon, using tetrahydro-thiopyran-4-onein place of 1-methylpiperid-4-one. The desired product was isolated as aglassy yellow oil (13.1 mg, 8.7% over three steps based on2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine starting material) bycolumn chromatography on SiO2, eluting with 4:1 EtOAc/MeOH.

δ_(H) (250 MHz, CDCl₃) 8.12 (1H, s, Ar), 7.34 (1H, d (apparent singlet),Ar), 6.81 (4H, m, Ar), 3.99 (2H, t, J 7.6, CH₂), 3.88 (2H, s, CH₂), 2.89(2H, d (apparent singlet), CH₂), 2.77 (2H, d (apparent singlet), CH₂),2.60 (2H, d (apparent singlet), CH₂), 2.48 (3H, s, CH₃), 2.39 (3H, s,CH₃); MS (ESI⁺): calc. m/z 323.1576, found 323.1585 (M+H⁺).

Synthesis 138-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-1,3,4,5-tetrahydro-pyrano[4,3-b]indole

8-Methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-1,3,4,5-tetrahydro-pyrano[4,3-b]indoleis prepared in an analagous manner to Dimebon, except thattetrahydro-pyran-4-one is used in the final step in place of1-methyl-piperidin-4-one.

REFERENCES

The following references are incorporated by reference herein in theirentirety:

-   U.S. Pat. No. 3,409,628-   U.S. Pat. No. 2,611,769-   U.S. Pat. No. 2,716,119-   WO02/075318-   Braak, H., Del Tredici, K, Braak, E. (2003) Spectrum of pathology.    In Mild cognitive impairment: Aging to Alzheimer's disease edited by    Petersen, R. C.; pp. 149-189-   Doody et al., The Lancet 2008, 372, 207-215.-   Flament et al. Brain Res. 1990, 516, 15-19.-   Harrington et al. Dementia 1994, 5, 215-228.-   Hof et al. Neurosci. Lett. 1992, 139, 10-14.-   Ikeda et al. Neurosci. Lett. 1995, 194, 133-135.-   Kost et al., J. Gen. Chem. USSR 1960, 30, 2538.-   Kost et al., Chemistry of Heterocyclic Compounds, 1973, 9, 191.-   Sperber et al., J. Am. Chem. Soc. 1959, 81, 704.-   Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash    and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott,    New York, USA).-   Handbook of Pharmaceutical Excipients, 2nd Edition (eds A. Wade    and P. J. Weller), 1994, American Pharmaceutical Association,    Washington and The Pharmaceutical Press, London.-   Medivation Form 10KSB filed 19 Feb. 2008.-   Novabiochem Catalog 2006/2007, UK Edition, Merck Biosciences.-   Remington: The Science and Practice of Pharmacy, 20th Edition (ed.    Gennaro et al.), 2000, Lippincott, Williams & Wilkins, Baltimore.-   Wischik et al. (in ‘Neurobiology of Alzheimer's Disease’, 2nd    Edition, 2000, Eds. Dawbarn, D. and Allen, S. J., The Molecular and    Cellular Neurobiology Series, Bios Scientific Publishers, Oxford.-   Yamashita et al., FEBS Letters 2009, 583, 2419-2424.-   Medivation press release, 4 Nov. 2009, ‘Medivation Reports Third    Quarter 2009 Financial Results and Provides Corporate Update’,    www.medivation.com. Ivachtchenko et al., Bioorg. Med. Chem. Lett.,    2009, 19, 3183-3187-   R. A. Jones, Aldrichimica Acta, 1976, 9(3), 35-45-   Masamichi Maruoka, Kakuzo Isgawa, and Yasaburo Fushizaki, “Nippon    Kagaku Zasshi”, 1961, 82, 1279-1284.

1.-57. (canceled)
 58. A method of preparing a compound of formula (II),said method comprising the step of: reacting a compound of formula (VI)

wherein -R⁶, -R⁷, -R⁸, and -R⁹ are each independently —H or —P^(A); -R¹⁰is independently —H or —P^(A); -L¹- is independently linear saturatedC₁₋₆alkylene; —P is independently pyridine or phenyl, optionallysubstituted with one or more groups —P^(A); each —P^(A) is independentlyselected from: -R^(B), —OR^(B), -L^(L)-OR^(B), —F, —Cl, —Br, —I, —CF₃,—OCF₃, —NO₂, —NR^(B) ₂, —NR^(BB)R^(BC), -L^(L)-NR^(B) ₂,-L^(L)-NR^(BB)R^(BC); and each -L^(L)- is independently saturatedaliphatic C₁₋₅alkylene; each -R^(B) is independently: -R^(B1), -R^(B2),-R^(B3), -R^(B4), -R^(B5), -L^(B)-R^(B2), -L^(B)-R^(B3), -L^(B)-R^(B4),or -L^(B)-R^(B5); wherein: each -R^(B1) is independently saturatedaliphatic C₁₋₆alkyl; each -R^(B2) is independently saturatedC₃₋₆cycloalkyl; each -R^(B3) is independently non-aromaticC₃₋₈heterocyclyl; each -R^(B4) is independently C₆₋₁₀carboaryl; each-R^(B5) is independently C₅₋₁₀heteroaryl; each -L^(B)- is independentlysaturated aliphatic C₁₋₃alkylene; and in each group —NR^(BB)R^(BC),R^(BB) and R^(BC), taken together with the nitrogen atom to which theyare attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring havingexactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one ofsaid exactly 2 ring heteroatoms is N, and the other of said exactly 2ring heteroatoms is independently N or O; to form a compound of formula(II):

wherein -R⁶, -R⁷, -R⁸, -R⁹-, -R¹⁰, L¹ and P are as defined for formula(VI).
 59. (canceled)
 60. The method according to claim 58, whereincompound (VI) is reacted with a reducing agent which is, or comprises,Bu₄NBH₄ to form compound (II).
 61. The method according to claim 58,wherein the reaction is performed at reflux in an organic solvent. 62.The reaction according to claim 58, wherein, after reaction, thereaction mixture is hydrolysed.
 63. The method according to claim 58comprising the steps of, in order: (iii) coupling a compound of formula(V):

wherein -L¹- is independently linear saturated C₁₋₆alkylene; —P isindependently pyridine or phenyl, optionally substituted with one ormore groups —P^(A); each —P^(A) is independently selected from: -R^(B)—OR^(B), -L^(L)-OR^(B), —F, —Cl, —Br, —I, —CF₃, —OCF₃, —NO₂, —NR^(B) ₂,—NR^(BB)R^(BC), -L¹-NR^(B) ₂, -L^(L)-NR^(BB)R^(BC); and each -L^(L)- isindependently saturated aliphatic C₁₋₅alkylene; each -R^(B) isindependently: -R^(B1), -R^(B2), -R^(B3), -R^(B4), -R^(B5),-L^(B)-R^(B2), -L^(B)-R^(B3), -L^(B)-R^(B4), or -L^(B)-R^(B5); wherein:each -R^(B1) is independently saturated aliphatic C₁₋₆alkyl; each-R^(B2) is independently saturated C₃₋₆cycloalkyl; each -R^(B3) isindependently C₃₋₈heterocyclyl; each -R^(B4) is independentlyC₆₋₁₀carboaryl; each -R^(B5) is independently C₅₋₁₀heteroaryl; each-L^(B)- is independently saturated aliphatic C₁₋₃alkylene; and in eachgroup —NR^(BB)R^(BC), R^(BB) and R^(BC), taken together with thenitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO; to form a compound of formula (VI); and reacting compound (VI) toform compound (II).
 64. The method according to claim 63, whereincompound (V) is coupled with a compound of formula (VII):

wherein -R⁶, -R⁷, -R⁸, -R⁹ and -R¹⁰ are as previously defined; to formcompound (VI).
 65. (canceled)
 66. The method according to claim 64,wherein compound (V) is coupled with compound (VII) using a couplingreagent which is a carbodiimide.
 67. The method according to claim 66,wherein the carbodiimide is DCC, EDC, or DIC.
 68. The method accordingto claim 64, wherein compound (V) is coupled with compound (VII) using acoupling reagent which is a haloformate.
 69. The method according toclaim 68, wherein the haloformate is iso-butyl chloroformate.
 70. Themethod claim 64, wherein a coupling reagent is used in combination witha phase transfer catalyst.
 71. The method according to claim 70, whereinthe phase transfer catalyst is Bu₄NBF₄.
 72. The method according toclaim 63 wherein a coupling reagent is used in combination with a base.73. The method according to claim 63 comprising the steps of, in order:hydrolysing a compound of formula (IV):

wherein -L¹- and P are as previously defined; Y is S or O. -R^(N1) and-R^(N2) are each independently —H or saturated C₁₋₆ alkyl, or -R^(N1)and -R^(N2) taken together with the nitrogen atom to which they areattached, form a 5-, 6-, or 7-membered non-aromatic ring having exactly1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of saidexactly 2 ring heteroatoms is N, and the other of said exactly 2 ringheteroatoms is independently N, O, or S; to form compound (V); couplinga compound of formula (V) to form a compound of formula (VI); andreacting compound (VI) to form compound (H).
 74. The method according toclaim 73, wherein compound (IV) is hydrolysed by reaction with a base toform compound (II).
 75. (canceled)
 76. The method according to claim 74,wherein the base is sodium hydroxide.
 77. (canceled)
 78. (canceled) 79.The method according to claim 73, wherein, after reaction, an amineby-product, NHR^(N1)R^(N2), is separated from compound (V), where-R^(N1) and -R^(N2) are as previously defined.
 80. (canceled)
 81. Themethod according to claim 73 comprising the steps of, in order: reactinga compound of formula (III)

wherein —P is as previously defined and -T¹ is independently linearsaturated C₁₋₆alkyl; to form compound (IV); hydrolysing a compound offormula (IV) to form compound (V); coupling a compound of formula (V) toform a compound of formula (VI); and reacting compound (VI) to formcompound (II).
 82. The method according to claim 81, wherein compound(III) is reacted with an amine, NHR^(N1)R^(N2), and a sulfinating agentto form compound (IV), where -R^(N1) and -R^(N2) are as definedaccording to the compounds of formula (IV).
 83. The method according toclaim 82, wherein the sulfinating agent is, or comprises, sulfur.
 84. Amethod of preparing a compound of formula (I):

wherein -R⁶, -R⁷, -R⁸, -R⁹, -L¹l, and —P are as previously defined; saidmethod comprising the method as defined in claim 57 of preparing acompound of formula (II), with the proviso that -R¹⁰ is H.
 85. Themethod of claim 84, further comprising the step of reacting compound(II) to form a compound of formula (VIII), wherein compound (VIII) is acompound:

wherein -R⁶, -R⁷, -R⁸, -R⁹, -L¹-, and —P are as previously defined, and-R¹⁰ is independently —H.
 86. The method of claim 85, compound (II) isreacted with nitrous acid to form compound (VIII).
 87. The method ofclaim 85 further comprising the step of reacting compound (VIII) to forma compound of formula (IX), wherein the compound (IX) is a compound:

wherein -R⁶, -R⁷, -R⁸, -R⁹, -L¹-, and —P are as previously defined, and-R¹⁰ is independently —H.
 88. (canceled)
 89. The method of claim 88,wherein compound (VIII) is reacted with a reducing agent selected fromzinc or LiAlH₄.
 90. The method according to claim 87, further comprisingthe step of reacting compound (IX) to form compound (I).
 91. The methodaccording to claim 90, wherein compound (IX) is reacted with a compoundof formula (X), wherein the compound (X) is a compound:

wherein -R¹, -R³ and X are as previously defined.
 92. The methodaccording to claim 91, wherein the compound (X) is selected from1-methyl-piperidin-4-one, tetrahydro-pyran-4-one andtetrahydro-thiopyran-4-one.
 93. A compound of formula (VI)

wherein —R⁶, -R⁷, -R⁸, and -R⁹ are each independently —H or —P^(A); —R¹⁰is independently —H or —P^(A); -L¹- is independently linear saturatedC₁₋₆alkylene; —P is independently pyridine or phenyl, optionallysubstituted with one or more groups —P^(A); each —P^(A) is independentlyselected from: -R^(B) —OR^(B), -L^(L)-OR^(B), —F, —Cl, —Br, —I, —CF₃,—OCF₃, —NO₂, —NR^(B) ₂, —NR^(BB)R^(BC), -L^(L)-NR^(B) ₂,-L^(L)NR^(BB)R^(BC); and each -L^(L)- is independently saturatedaliphatic C₁₋₅alkylene; each -R^(B) is independently: -R^(B1), -R^(B2),-R^(B3), -R^(B4), -R^(B5), -L^(B)-R^(B2), -L^(B)-R^(B3), -L^(B)-R^(B4),or -L^(B)-R^(B5); wherein: each -R^(B1) is independently saturatedaliphatic C₁₋₆alkyl; each -R^(B2) is independently saturatedC₃₋₆cycloalkyl; each -R^(B3) is independently non-aromaticC₃₋₈heterocyclyl; each -R^(B4) is independently C₆₋₁₀carboaryl; each-R^(B5) is independently C₅₋₁₀heteroaryl; each -L^(B)- is independentlysaturated aliphatic C₁₋₃alkylene; and in each group —NR^(BB)R^(BC),R^(BB) and R^(BC), taken together with the nitrogen atom to which theyare attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring havingexactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one ofsaid exactly 2 ring heteroatoms is N, and the other of said exactly 2ring heteroatoms is independently N or O.
 94. A compound of formula (I)

wherein —R⁶, -R⁷, -R⁸, and -R⁹ are each independently —H or —P^(A) —R¹⁰is independently —H; -L¹- is independently linear saturatedC₁₋₆alkylene; —P is independently pyridine or phenyl, optionallysubstituted with one or more groups —P^(A); each —P^(A) is independentlyselected from: -R^(B), —OR^(B), -L^(L)-OR^(B), —F, —Cl, —Br, —I, —NO₂,—NR^(B) ₂, —NR^(BB)R^(BC), -L^(L)-NR^(BB) ₂, -L^(L)-NR^(BB)R^(BC); andeach -L^(L)- is independently saturated aliphatic C₁₋₅alkylene; each-R^(B) is independently: -R^(B1), -R^(B2), -R^(B3), -R^(B4), -R^(B5),-L^(B)-R^(B2), -L^(B)-R^(B3), -L^(B)-R^(B4), or -L^(B)-R^(B5); wherein:each -R^(B1) is independently saturated aliphatic C₁₋₆alkyl; each-R^(B2) is independently saturated C₃₋₆cycloakyl; each -R^(B3) isindependently non-aromatic C₃₋₈heterocyclyl; each -R^(B4) isindependently C₆₋₁₀carboaryl; each -R^(B5) is independentlyC₅₋₁₀heteroaryl; each -L^(B)- is independently saturated aliphaticC₁₋₃alkylene; and in each group —NR^(BB)R^(BC), R^(BB) and R^(BC), takentogether with the nitrogen atom to which they are attached, form a 4-,5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatomor exactly 2 ring heteroatoms, wherein one of said exactly 2 ringheteroatoms is N, and the other of said exactly 2 ring heteroatoms isindependently N or O; and wherein -R¹ and -R³ are each independently —Hor -R^(A); X is selected from O, S, S(O) or S(O)₂; each -R^(A) isindependently: -R^(A1), -R^(A2), -R^(A3), -R^(A4), -R^(A5),-L^(A)-R^(A2), -L^(A)-R^(A3), -L^(A)-R^(A4), or -L^(A)-R^(A5); wherein:each -R^(A1) is independently saturated aliphatic C₁₋₆alkyl; each-R^(A2) is independently saturated C₃₋₆cycloalkyl; each -R^(A3) isindependently non-aromatic C₃₋₈heterocyclyl; each -R^(A4) isindependently C₆₋₁₀carboaryl; each -R^(A5) is independentlyC₅₋₁₀heteroaryl; each -L^(A)- is independently saturated aliphaticC₁₋₃alkylene; and wherein: each C₁₋₆alkyl, C₃₋₆cycloalkyl, non-aromaticC₃₋₈heterocyclyl, C₆₋₁₀carboaryl, C₅₋₁₀heteroaryl, and C₁₋₃alkylene isoptionally substituted, for example, with one or more substituents; andthe dashed line indicates that the bond is a single bond or a doublebond between the 4a and 9a atoms.